cytokines and prostaglandins in immune homeostasis and tissue destruction in periodontal disease
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8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
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PeriodonroIogy2000. Vol. 14. 1997,112 143
Printed in Denmark . All rights reservedC o p y r i g h t M u n k s g a a r d 1997
PERIODONTOLOGY 2000ISSN 0906-6713
Cytokines andprostaglandinsin
immune homeostasisandtissuedestructioninperiodontaldisease
E R I CA E MM E L L ,ODERICK. M A R S H A L LGREGORY. S E Y M O U R
Immune homeostasisinperiodontaldisease
Chronic inflammatory periodontal disease manifests
clinically as at least two distinct entities. Evidence
based on microbiological, immunological and ani-
mal model studies has shown that some forms of
periodontal disease in adults can remain stable over
many years and not endanger the life of the den-
tition, whereas other forms, despite extensive treat-
ment, continue to break down, leading ultimately to
tooth loss (279). Periodontal disease is caused by
bacteria in dental plaque, and evidence is increasing
that specific periodontal pathogens are associated
with the progressive form of the disease. However,
some individuals harbor these specific microorgan-
isms but do not appear to show evidence of disease
progression. Patient susceptibility is of utmost im-
portance to the outcome of periodontal disease, and
although periodontal bacteria are the major etiolog-
ical agents, the host immune response to these bac-
teria is of fundamental importance (280).
Susceptibility to periodontal disease is most likely
genetically determined, although a number of local
and environmental factors such as smoking, recent
viral infections and physical and mental stress arethought to influence disease expression (280).Gen-
etic factors divide the population into susceptible
and nonsusceptible people, and individuats may be
in balance with their oral flora as manifested by a
stable lesion and only when the balance is disrupted
by, for example, the appearance of a microorganism
such as Porphjironiotiris girzgiimlis or by depression
of the irnmirne response a s a t.esult of environmental
factors does progression occur. Whether this applies
only to susceptible individuals remains t o be deter-
mined 280).
Periodontal disease results from the interaction of
the host’s defense mechanisms with microorganisms
in plaque, and the immune responses associated
with the pathology of the disease have been the basis
of study for the past 30 years. Histological studies
support the concept that the immune system re-
sponds to plaque microorganisms. The infiltrate in
the periodontal lesion consists of lymphocytes and
macrophages; whereas T lymphocytes predominate
in the stable lesion, the proportion of B cells and
plasma cells is increased in the progressive lesion
(279, 280). Functional assays using peripheral blood
lymphocytes have contributed to the understanding
of the disease process by highlighting a role for T
cells. Most work on immunoregulation of chronic in-
flammatory periodontal disease has therefore fo-
cused on T cells (282). Studies have shown a de-
pressed CD4:CD8 ratio in cells extracted from adult
periodontitis lesions compared with peripheral
blood and healthy tissue or tissue with gingivitis 41,
3031, and T cells extracted from diseased periodontal
tissues have a reduced ability to respond in an auto-
logous mixed lymphocyte reaction (421, suggesting a
suppression of cell-mediated responses. Seymour et
al. (281) demonstrated a lack of interleukin 2 (IL-2)
production by unstimulated T cells extracted from
adult periodontitis patients and suggested this as areason for the failure of these cells to undergo spon-
taneous proliferation (41). In support of this study,
a reduced production of IL-2 andlor IL-2 receptor
expression by T cells in patients with a reduced auto-
logous mixed lymphocyte reaction has recently been
reported (155). Interestingly, the autologous mixed
lymphocyte reaction has been reported to return to
normal following periodontal therapy (296).
Although patient susceptibility is most likely of
major importance in determining the outcome of
periodontal disease, the problems in detecting sus-
ceptible individuals have not been solved. Such func-
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Cytokines and prostaglandins in periodontal disease
tional studies as proliferation assays or the auto-
logous mixed lymphocyte reaction are not suitable, as
not all individuals with severe disease have a de-
pressed proliferation to periodontal pathogens or a
reduced autologous mixed lymphocyte reaction
(280).There is a great dealof variation in the microbialcomposition between individuals and also from site
to site in the same individual, as well as variation with
respect to the frequency and rate of progression of
periodontal disease (280).A study of cytokines in peri-
odontal disease lesions may throw some light on this
problem and may suggest future lines of therapy.
Immune homeostasis
Cytokines are cell regulators that have a major in-
fluence on the production and activation of different
effector cells. T cells and macrophages are a major
source, although they are produced by a wide range
of cells that play important roles in many physiologi-
cal responses. Cytokines are low-molecular-weightproteins involved in the initiation and effector stages
of immunity and inflammation, in which they regu-
late the amplitude and duration of the response.
They are usually produced transiently, are extremely
potent, generally acting at picomolar concentrations
and interact with specific cell surface receptors,
which are usually expressed in relatively low num-
bers (11). Some cytokines are produced by a re-
stricted type of cell, such as IL-2 produced by T cells,
The type of immune response that occurs on ex-
posure to a pathogen is vital in determining resist-
ance or susceptibility to disease. The importance of
the cytokines induced locally is paramount due to
their different effects on the function of cells in the
immediate neighborhood, which then determines
the course of the response and hence the resistance
or susceptibility to the particular pathogen (28).
Cytokines are recognized as being vital in the im-
munopathology of an ever-increasing number of dis-
eases, and the production of “appropriate”cytokines
is essential for the development of protective im-
munity. If “inappropriate” cytokines are elicited, de-
whereas others, including IL-1 and IL-6, re pro-
duced by very different cell types. Also, target cells
may be restricted or very diverse (123).Many cyto-
kines are pleiotropic, having multiple activities on
different target cells and or overlapping cell regula-
tory actions, but despite this overlap, cytokine func-
tions may not be identical (123). The response of a
cell to a given cytokine depends on the local concen-
tration, the cell type and other cell regulators to
which it is constantly exposed. Cytokines interact in
a network first by inducing each other; second by
transmodulating cell surface receptors: and third by
synergistic, additive or antagonistic interactions on
structive or progressive disease can result (151) (Fig.
1).Just how the immune system selects the right re-
sponse to a particular pathogen is not clear (208).
However, the determination of the features of both
the host and pathogen that direct how and where the
organism is presented to cytokine-producing cells is
necessary in understanding the pathogenesis of all
infectious diseases 151).
cell function 11).
The majority of immune responses occur locally
rather than systemically within a small area of tissue
and often between two cells that are conjugated to
one another (206). Since the discovery of IL-2 in
1976,more than twenty cytokines have been char-
acterized that are essential for many of the prolifer-
ative and differentiative functions of immune cells
206). hus, there appears to be a very complex net-
work of interactions within the immune system.
Mosmann (206) believes that this complexity is es-
sential for overcoming the various defense strategies
of microorganisms.As microorganisms evolve morerapidly than their mammalian hosts, a single im-
mune mechanism could not cope with any new
product synthesized by an infectious agent that in-
terfered with an essential link between cells. Multiple
regulatory mechanisms may therefore be a defense
against pathogen interference and hence could be
essential in the preservation of homeostasis.
Thl and Th2 paradigm
A successful immune response to an infectious agent
depends on activation of appropriate effector func-
Fig. 1. The production of appropriate or inappropriate
cytohes determines aserne expression. Ag: antigen;
A P C antigen-presenting cell
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Gemmell et al.
tions (243). Extracellular pathogens are generally
eliminated by antibody binding, which facilitates
complement fixation, phagocytosis and activation of
the Fc receptor-dependent release of reactive oxygen
species by monocytes or macrophages and polymor-
phonuclear neutrophils 151). Elimination of intra-cellular pathogens (viruses and certain bacteria), de-
pends on the destruction of the infected cell by anti-
gen-specific cytolytic T cells and activated
macrophages (151). Inactivation of other organisms
occurs by the release of enzyme-rich granules from
eosinophils and mast cells as in the case of hel-
minths, intracellular lysis in the case of infection of
macrophages by bacterial pathogens such as Listeria
monocytogenesor some protozoan parasites such as
Leishmania major, or by sequestration in granu-
lomas as in mycobacterial and schistosorne infec-
tions (151).
Cell-mediated immune responses involve the acti-
vation of macrophages and induction of different
0 4 ' and CD8+ T cells, whereas humoral immunity
is characterized by antibody production. These two
responses were originally classified in the mouse as
being regulated by two distinct subsets of CD4+
helper T cells, termed Thl and Th2 cells, which se-
crete different patterns of cytokines (207). Thl cells
produce 1L-2, interferon (IFN-y) and tumor necrosis
factor p, while Th2 cells are defined by the produc-
tion of IL-4, IL-5, IL-6, IL-10 and IL-13. Both cell
types produce IL-3, tumor necrosis factor a and
granulocyte-macrophage colony-stimulating factor
(152). Human CD4' T cells have cytokine patterns
and functions comparable to those that exist in
mice, although the synthesis of IL-2, IL-6 I L - I 0 and
IL-13 are not as restricted to a single subset as in the
mouse T cell (208). Thl cytokines are involved in
cell-mediated inflammatory reactions. They increase
the ability of macrophages to lull intracellular and
extracellular pathogens and also mediate delayed-
type hypersensitivity reactions (208). Th2 cytokines
are found in association with strong antibody andallergic responses. These cells stimulate mast cells,
eosinophils and immunoglobulin E (IgE) antibodies
and are elevated in allergic diseases and helminth
infections (258). Thl and Th2 cells play different
roles, not only in protection against exogenous anti-
gens, but also in irnmunopathology (258). Therefore
each T-helper subset induces and regulates effector
functions targeted at different antigens and patho-
gens. Although most studies have been on CD4'
cells, it has been reported that the majority of CD8'
T cells have a Thl-like profile. These T cells are cyto-
toxic, and although the pattern of secretion is Thl,
Fig. 2. The balance between suppressorand cytotoxic CD8
T cells may be due to t he level of IL-I0 production
IL-2 secretion is low or undetectable (295). IFN-y is
secreted at about the same level as CD4+ Thl clones,
whereas most other cytokines are secreted at lower
levels. There is evidence that Th2-like CD8+ T cells
also occur in both the human and mouse (20). lnoue
et al. (143) showed that cytolytic CD8+ T cells could
not suppress CD4+ T cells, whereas suppressor
CD8+ T cells could suppress the proliferative re-
sponses of both Thl and Th2 CD4+ cells by the pro-
duction of IL-10 (Fig. 2). IL-4-secreting CD8+ cells
from lepromatous leprosy patients have been shown
to suppress the proliferation of leprosy-specific
CD4+ T-cell clones, and this depended on 1L-4 (269).
Mingari et al. (198) found that their IL-4/IL-5 or
their IL-2-producing CD8+ clones were cytolytic and
that these clones appeared to co-express helper and
cytolytic functions. However, whether CD8+ Type 2
cells provide cognate help for B cells as do CD4+
cells has yet to be reported. What is now evident is
that the pattern of cytokine production by both
CD4' and CD8+ T cells appears to be related to the
function of the cell rather than to the phenotype
(20).
Immune factors that contribute to the manifes-
tations of infectious diseases remain a mystery (202).
Individuals may develop a cellular immune response
resulting in containment or elimination of the infec-
tion. In some susceptible individuals the infection
proceeds unabated due partly to a defect in the
cellular response but not the humoral response,which is usually intact (202). CD4+ T cells play a
major role in protection against parasitic infection
and also in inducing the pathology associated with
the infection (295). The immune response to infec-
tion is regulated by the balance between Thl and
Th2 cytokines. Many recent studies have focused on
the cytokines responsible for immunity or pathology.
The net effect of the Thl cytokines IL-2 and IFN-y is
to enhance cell-mediated responses, whereas that of
the Th2 cytokine IL-4 is to suppress cell-mediated
responses and hence enhance the resistance associ-
ated with humoral immunity (202). However, cyto-
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Cytokines and prostaglandins in periodontal disease~
Fig.
sors for both Thl and Th2 cells.Ag: antigen
Previous concept in which Tho cells were precur-
kine concentration can also affect the outcome of a
response. Low levels of IFN-y produced by Thl cells
in mice induce antibody with an immunoglobulin
G2a (IgG2a) isotype, but high levels of this cytokine
inhibit B-cell responses. The result of Thl interac-
tion can therefore be help or suppression of anti-
body production. Th2 clones provide help for the
formation of IgM, IgGl (mouse) or IgG4 (human),
IgA and IgE because of the production of the B-cell
proliferation and differentiation factors, IL-4, IL-5
and IL-6 (295). IFN-y, on the other hand, inhibits the
IL-4-induced IgE response (39).In uiuo studies using
cytokines and anti-cytokine antibodies have sup-
ported these observations, providing support for the
concept that the functional abilities of the Thl and
Th2 subsets are due mainly to the cytokines they
produce (295).
The Thl and Th2 model has recently come under
attack as being too simplified. Murine and human T-
cell clone cytokine profiles not fitting this classifi-
cation have been reported (152). Murine IL-2- and
IL-4-producing clones can be derived from the same
cells, suggesting that cytokine phenotype is acquired
during T-cell differentiation and is not secondary to
the expansion of distinct subpopulations predeter-mined to produce a specific cytokine pattern (257).
Most resting T cells secrete IL-2 when first stimu-
lated and then differentiate into cells secreting a
number of cytokines (206). Several secretion pat-
terns seen in short-term in uitro clones that are
clearly not Thl or Th2 may represent early stages
in the differentiation pathway, and the Thl and Th2
cytokine profiles are assumed to represent final
chronically stimulated helper T cells (295). A third
category of T-helper cell clones designated Tho cells
produce a mix of Thl and Th2 cytokines. Until now
it has been believed that, on activation, antigen-spe-
cific naive T cells develop into Tho cells and then
differentiate further into Thl or Th2 cells with re-
peated antigen stimulation (202) (Fig. 3). This pro-
gression through a stage of unrestricted gene ex-
pression is now open to question (152), and Tho cells
may represent other subsets depending on the com-
bination of cytokines. Kelso et al. (153) have shown
that any possible combination of cytokines can be
secreted by individual clones, indicating a random
association between cytokines. Differences in cyto-
kine expression may represent distinct phenotypes,
developmental stages or transient phases in re-
sponse to conditions such as the presence of modi-
fying influences. Mosmann Sad (208) feel, how-
ever, that many T-cell clones and in viuo responses
do show the dichotomy of IL-2 and IFN-y and IL-
4, IL-5 and IL-10 responses and believe it to be an
important dichotomy in the immune response.
Carter Dutton (28) report that there is a natural
tendency towards polarization of T-cell clones and
find it difficult to understand how polarized popula-
tions could be generated if, as suggested by Kelso
(152),an independent regulatory process determines
the secretion of each cytokine.
The balance between local levels of cytokines is
important in determining the outcome of an im-
mune response. The question as to whether acti-
vated T cells can be classified into Thl, Th2 or Tho
subsets wiU not be solved until the presence of as
yet uncloned cytokines that play a role in immunity
has been determined. This classification is con-
venient for now, and what should be kept in mind is
the significance of individual cytokines in the re-
sponse under investigation, and the naming of the
particular T-cell subsets producing them is really a
minor factor. However, many immune responses
seem to involve predominant Thl or Th2 cytokines
(152),and the functional outcome may best be pre-
dicted by the cytokines involved and their respective
antagonists (Fig. 4).
Major cytokines relating to the Thl and Th2paradigm
Interferon gamma. Interferons were first character-
ized as substances that inhibit virus replication, al-
though it is now known that they have many immu-
nomodulatory activities. IFN-y is different in both
biochemistry and biological properties from IFN-a
and IFN-J3 and, whereas the latter are produced by
cells infected with virus, IFN-y is produced during
an immune response by antigen specificT cells and
natural killer cells recruited by IL-2 (225).Its regula-
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Cvtokines and vrostaalandins in veriodontal disease
Table 1.Summary of major Thl and Th2 cytokine functions
Cytokine Source Functions
Interferon y T cells requisite for induction of Thl cellsnatural killer cells inhibits interleukin 4 activities
enhances interleukin 12 production
stimulates macrophage activity, cytolytic T lymphocytes and natural killer cellsup re da te s class I and 11major histocompatibilitv complex molecules
Interleukin 4 T cells induces Th2 cell differentiationmast cellsbasophils inhibits interleukin 12 production
inhibits interleukin 2- and interferon y-induced activities
induces proliferation and differentiation of B cellsinduces proliferation of T cellsdownregulates monocyte production of interleukin 1, tumor necrosis factor a
and interleukin 6
Interleukin 10 T and B cellsmonocytes and
macrophages
promotes Th2 esponses while suppressingThl cell-mediated responsessuppresses proliferation and cytokhe production by activated T cellssuppresses macrophage function and interleukh 12 productioninhibits macrophage-derived interleukin lu, interleukin 6 and interleukin 8enhances interleukin Ira productionenhances B-cell proliferation and differentiation
~ ~~ ~ ~
Interleukin 12 B cells plays a key role in Thl induction
stimulates growth and cytotoxic activity of natural killer and T cellsprovides a link between natural resistance mediated by phagocytic cells andmonocytes andmacrophagesdendritic cellskeratinocytesLangerhans cellsneutrophils
natural killer cells and adaptive immunity mediated by T-helper cells,cytolytic T lymphocytes and B cells
Interleukin 13 T cells similar functions to interleukin4 although more restricteddownreguIates interleulrin 12 production and, like intedeukin 4
acts as a co-stimulatory signal for human B cells but does not affect T cellsmodulates monocyte and macrophage function including inhibition of
may favor Th2 development
cvtoldne Droduction
towards CD8+ T cells while suppressing the ability
of CD4+ T cells to migrate in response to IL-8 (148).
IL-10 is a potent growth and differentiation factor for
activated human B cells and may therefore play an
important role in amplifying the hurnoral immune
response (264). The synthesis of monocyte-derived
pro-inflammatory cytokines including IL-1-a, IL-6
and IL-8 is inhibited by IL-10, which also enhances
the production of the IL-1 receptor antagonist (IL-
Ira) so that this cytokine dampens immune prolifer-
ation and inflammatory responses (54).
Although both Thl and Th2 cells produce and can
be inhibited by IL-10, it would appear that, in gen-eral, IL-10 promotes Th2 responses while sup-
pressing delayed-type hypersensitivity reactions and
other Thl cell-mediated responses. As a potent anti-
inflammatory reagent, IL-10 is being reviewed in the
light of diminishing the pathology associated with
a number of diseases such as rheumatoid arthritis,
bacterial sepsis and psoriasis (138) (Table 1).
Interleukin 12. IL-12 was originally described as a
factor promoting natural killer and cytolytic T cells
activity. It is produced mainly by monocytes and
macrophages, dendritic cells and polymorpho-
nuclear neutrophils with keratinocytes, Langerhans
cells and B cells producing only low levels (166). L-
12 provides a link between natural resistance med-
iated by phagocytic cells and natural killer cells and
adaptive immunity mediated by T-helper cells, cyto-
lytic T cells and B cells (311). IL-12 has pleiotropic
effects on natural killer cells and T cells. These in-
clude the enhancement of natural killer and T-cell
cytotoxic activity and enhancement of T-cell and
natural killer-cell proliferation after activation by
other stimuli (159,238). IL-12 induces IFN-y produc-
tion by resting and activated T and natural killer cells
(34,159). The early production of 1L-12 representsa key process in natural killer activation and innate
resistance. Natural killer cells can influence the path-
way of Thl and Th2 development when antigen-spe-
cific T cells start to undergo clonal expansion and
differentiation. In this context, natural killer cells
may represent an early source of IFN-)I, which would
contribute to the development of a Thl response.
They appear to be most effective in preventing early
infection, but T and B cells and their products are
required to resolve the infection (12).
Studies have demonstrated that IL-12 plays a key
role in the differentiation of Thl cells. It acts directly
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Gemmell et al.
on both Thl cells and on their precursors, and part
of this activity is due to the induction of IFN-y pro-
duction by T and natural killer cells. IFN-y has a
positive feedback effect by enhancing the produc-
tion of IL-12 by monocytes and macrophages,
whereas the cytokines IL-4 and IL-10 are powerfulinhibitors of IL-12 production. I t has been suggested
that IL-12 may be the IL-4 equivalent for the differ-
entiation of Thl cells, and these two cytokines may
determine the balance of Thl and Th2 cells (311)
(Table 1). However, this would appear to oversimpl-
ify the situation. It has recently been demonstrated
that IL-12 addition to T-cell cultures during acti-
vation can also result in the promotion of the
2 cytokine IL-4 in addition to IFN-y with or without
IL-10 (166) and to potentiate established Th2 re-
sponses by increasing the proliferation and IL-4 pro-
duction of established Th2-like T-cell clones (147).
These results bring into question the central role of
IL-12 in Thl commitment.
As well as being protective, IL- 12 can also promote
detrimental effects. The administration during ex-
perimental viral infections of doses of IL-12 re-
portedly beneficial in other infections resulted in ad-
verse effects, including inhibition of cytolytic T-cell
activity and virus-induced CD8' T-cell expansion;
the accompanied induction of tumor necrosis factor
was a pivotal factor in the ensuing pathology (230).
Lower doses of IL-12 enhanced CD8+ expansion and
the clearance of virus. This study demonstrated the
potential complications arising from IL- 12 adminis-
tration during an ongoing immune response.
interleukin 13. IL-13 is a potent modulator of hu-
man monocyte and B-cell function. This cytokine is
secreted by both CD4' and CD8+ human T-cell
clones, the CD4+ cells having Tho, Th l and Th2 pro-
files. IL-13 is produced early after activation and over
prolonged periods of time, in contrast to IL-4, which
is secreted much later and occurs transiently (337).
Monocyte cell surface markers including CD23,
major histocompatibility complex class I1 and sev-
eral integrin molecules are upregulated by IL- 13 (55).
The production of the cytokines IL-1 a, IL-1 p, 1L-6,
IL-8 and tumor necrosis factor a induced by lipo-
polysaccharide-stimulated human monocytes is also
inhibited by IL- 13, whereas IL-1 receptor antagonist
secretion is enhanced (55, 337). Therefore IL-13,
along with IL-4 and IL-10, would appear to have po-
tential anti-inflammatory activity (337).Although IL-
13 appears to mimic IL-4, its biological activities are
more restricted than IL-4. t does not, for example,
act o n human or mouse T cells nor on mouse B cells.
although it does act as a co-stimulatory signal for
human B cells (193).
Like IL-4, IL-13 may favor the development of Th2
responses as it downregulates the production of IL-
12. Also like IL-4, IL-13 induces IgG4 and IgE syn-
thesis and directs IgE isotype switching in humans(245). IL-13 and IL-4 genes are closely linked in both
the human and mouse genomes and there is se-
quence homology between the secreted proteins.
The IL-4 and IL-13 receptors also share a common
subunit, although the IL-4 receptor does not bind IL-
13. The production of an IL-4 mutant protein to act
as a receptor antagonist for both IL-4 and IL-13 may
have therapeutic value in the treatment of Th2-pre-
dominant infections (337) (Table 1).
Cytokine regulation
The products of Thl and Th2 cells play a major role
in the regulation, differentiation and subsequent ef-
fector functions of the reciprocal subset (243). Differ-
entiation andlor growth of Thl cells can be inhibited
during a strong Th2 response and vice versa. The
cytokines IFN-y, IL-4, IL-10 IL-12 and IL-13 recipro-
cally regulate the proliferative and cytokine secreting
abilities of T-cell subsets (295). The mechanisms by
which certain T-cell subsets are induced are still
poorly understood (20).I t is possible to bias the type
of immune response to achieve a desired outcome
(20). Several factors are thought to influence the de-
velopment of T-cell subsets, including the antigen it-
self, its concentration and the route of administra-
tion (277). On challenge, priming of mice with inacti-
vated virus or subunit F glycoprotein of respiratory
syncytial virus was shown to induce a Th2-like
lymphocyte response, whereas challenge of mice
primed with live respiratory syncytial virus by par-
enteral or mucosal routes induced a Thl pattern of
cytokine messenger RNA (116). Oral immunization
of mice with sheep red blood cells induced predom-
inantly IL-5-producing Th2-type cells in the Peyer's
patches and spleens, whereas spleen cell cultures of
intraperitoneally immunized mice exhibited a high
proportion of IFN-y-producing cells (328). Oral im-
munization with tetanus toxoid and cholera toxin (a
powerful mucosal immunogen) as adjuvant, selec-
tively induced Th2 cells in mucosa-associated
tissues (329). Adjuvants themselves are able to trig-
ger either CD4' (Thl and Th2) or CD8 T-cell devel-
opment and so modulate selectively the production
of cytokines (10).
The nature of the interaction with the T-cell recep-
tor may also determine cytokine profiles (51). T-cell
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Cytokines and prostaglandins in p eriodontal disease
receptor-ligand interaction is decisive for the com-
mitment of peripheral blood CD4+T cells toward a
Thl or Th2 response (256). Stimulation of a mouse
CD4 cell clone by three different antigens resulted in
similar levels of proliferation, but only physiological
recognition of major histocompatibility complexclass I1 products plus antigenic peptide or allorecog-
nition of a major histocompatibility complex class I1
alloantigen but not recognition of an Mls-la super-
antigen in association with several major histocom-
patibility complex class I1 products resulted in IFN-y
production (234). Major histocompatibility complex
molecules may also therefore influence the develop-
ment of T-cell subsets. In this context, a single pep-
tide epitope derived from human type IV collagen
has been shown to depend on major histocompat-
ibility complex class I1 expression (277). Thl re-
sponses were observed in H-2s mice, whereas Th2
responses were seen in H-2b mice, suggesting that
quantitative differences in major histocompatibility
complex class I1 binding of antigen may influence
the T-cell response (277).
It is becoming recognized, therefore, that the anti-
gen-presenting cells may influence which T-cell sub-
set is induced. Brain microvessel endothelial cells
and smooth musclelpericytes respectively activate
Th2 and Thl cell clones Preferentially (88). Hepatic
accessory cells support the proliferation of Thl but
not Th2 cells (295). Evidence suggests that B cells
direct CD4+ T cells to a Th2 pathway (20). This is
supported by a study demonstrating the clonal ex-
pansion of ovalbumin-specific Thl and Th2 cells to
be preferentially stimulated by antigen-presenting
adherent cells (macrophagesand dendritic cells) and
antigen-presentingB cells respectively (98). CD5+ B
cells have been suggested as candidates for antigen
presentation to suppressor T cells, indicating that
they may be involved in the induction of a Th2 re-
sponse 20).
Thl and Th2 paradigm inperiodontal disease
A number of studies have reported on the presence
of cytokines in periodontal disease. Pilon et al. (240)
demonstrated lower levels of IL-2 in gingival crevic-
ular fluid of periodontitis sites compared with
healthy sites, and Fujihashi et al. 95) have shown
that gingival mononuclear cells from adult peri-
odontitis patients produce IL-4 and IL-5 but not IL-
2. Significantly less IL-2 activity was found in periph-
eral blood mononuclear cell cultures stimulated by
two putative periodontal pathogens, I gingivalis and
Fusobacteriurn nucleaturn, than in unstimulated cul-
tures (104). In this study, IFN-y as measured by an
immunoassay could not be detected in cultures con-
taining both bacteria and, furthermore, IFN-y wasdemonstrated in only 10/27 gingival mononuclear
cell culture supernatants. Only negligible amounts
were found in 50 of these positive cultures. IL-12
has been found to be significantly reduced in gingi-
val tissue extracted from sites of probing depths
greater than 6 mm compared with tissue from sites
between 3 and 6 mm and normal healthy tissue (83).
These results all suggest decreased Thl responses in
advanced periodontitis.
Memory T cells from the peripheral blood of adult
periodontitis patients with high anti-I?gingiuulis tit-
ers stimulated in uitro with P gingivufis have been
shown to produce higher amounts of IL-4 than do
cells from healthy subjects (4). In this study, no IL-4-
producing memory T cells were detected in healthy
gingival tissues, and a larger proportion of peripheral
blood memory T cells from patients in which high
frequencies of IL-4-producingcells were identified in
the lesion produced IL-4 following stimulation with
antigen. Yamazaki et al. (333) demonstrated an in-
creased percentage of IL-4-positive cells pro-
portional with an increasing ratio of B cells to T cells.
IL-4 was the prominent cytokine in periodontally
affected tissues compared wi th IL-2, IFN-y and IL-6.
The demonstration of concentrations of IgG4 many
times higher in sites of active periodontitis than in
serum as well as significantly elevated concen-
trations compared with stable lesions also suggests
a role for IL-4 and Th2 responses in periodontitis
lesions (252).
A cell dot-blot analysis of cytokine-producing gin-
gival mononuclear cells showed a higher percentage
of unstimulated periodontal disease cells were IL-4
positive and a higher percentage of cells were IL-2
and IL-4 positive when stimulated with €? gingivulis(183). Analysis of IL-2:IL-4 ratios revealed signifi-
cantly lower ratios for cells derived from peri-
odontitis tissues compared with cells from gingivitis
tissues. Taken together, these data seem to support
the hypothesis that Thl cells are associated with the
stable lesion, whereas a Th2 response may lead to
nonprotective antibodies and disease progression.A
Th2 response that results in protective antibodies
may result in elimination of organisms (104, 282). In
contrast, Ebersole Taubman (74) found that the
IFN-)I message was prominently expressed by dis-
eased gingival tissue cells. Cytokine profiles of cells
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Gemmell et al.
extracted from 6 patients were consistent with Thl
cells in that they were IL-2 and IFN-y positive but
negative for IL-5. A further sample had messages for
IL-2 and IL-5, consistent with Tho cells. This study
speculated that Thl cells may be destructive in peri-
odontal disease via the production of IFN-y and po-tential stimulation of macrophage secretion of IL-1
with subsequent bone resorption. However, the pres-
ence of messenger RNA for IFN-.I, IL-6 and IL-13 but
not for IL-2, IL-4 or IL-5 in CD4+ T cells extracted
from periodontal disease lesions indicates that Tho
cells may be involved in periodontal disease (96).
Takeichi et al. (299) showed that IFN-y and IL-1-p
messenger RNA was expressed by some gingival cells
on extraction, indicating Type 1 cells, and upon
stimulation, IL-6 transcripts were also expressed but
no IL-2 or IL-2 receptor messenger RNA could be
detected. Yet another study on IL-2, IL-4, IL-6, IL-10, IFN-a and I F N - ~ I xpression found no skewing of
cytokines towards a Thl or Th2 profile in diseased
or healthy tissues, although there was a significantly
higher expression of IL-6 and IFN-a messenger RNA
in diseased tissues (244).
T-cell lines and clones specific for I? gingiuulis
have been reported to resemble Tho cells, although
one CD4-positive clone did produce IL-4 and IL-5
messenger RNA, suggesting a Th2 profile (150). An-
other study showed that F gingivalis-reactive T-cell
lines derived from the peripheral blood of a I? gingi-
vulis-infected adult periodontitis and a gingivitis
subject and from the gingival tissues of the adult
periodontitis patient, contained both the Th2 cyto-
kine, IL-4 and the Thl cytokines IFN-)I and IL-2, al-
though there was a higher percentage of IL-4-posi-
tive T cells in the adult periodontitis-derived lines
(102).These data may therefore indicate that the full
range of cytokine-producing T cells (Tho, Thl and
Th2) are all found in both gingivitis and periodontitis
lesions, or may in fact offer supporting evidence for
the concept that such distinction of T cells does not
in reality exist (152). Nevertheless, the Thl ITh2 para-
digm has provided an excellent framework for the
investigation of cytokines in periodontal disease.
Emerging from these studies is the concept that IL-
10 may be of fundamental importance in the control
of periodontal disease progression (Fig. 5). For ex-
ample, only adult periodontitis T-cell lines and de-
rived clones produced IL-10 (102). Stein Hendrix
(294) have also shown a role for IL-10 in periodontal
disease by demonstrating that gingival mononuclear
cells extracted from adult periodontitis patients pro-
duce more IL-10 than cells derived from nonin-
flamed tissue. As well, anti-IL-10 antibodies induced
Fig. 5. The possible role of IL-10 in periodontal disease
homeostasis
an 80970 decrease in the frequency of anti-collagen-
secreting cells, and these authors suggested that IL-
10 in inflamed gingival tissues potentiates a local
autoimmune response characterized by an increase
in the frequency of anti-collagen secreting cells. Arole for IL-10 has also been suggested by another
study that used reverse transcriptase polymerase
chain reaction to analyze cytokine expression in
CD4-positive gingival lymphocytes isolated from in-
flamed periodontal tissues. Two distinct profiles
were noted. One pattern showed the presence of
IFN-y, IL-6, IL-10 and IL-13 messenger RNA; the
other pattern was similar with the exception of a lack
of IL-10 messenger RNA. In most cases, IL-2, IL-4
and IL-5 messenger RNA were not detected (330).
Determination of the correlation of the absence or
presence of IL-10 with the progression of disease
may be worthy of further attention.
Cytokine control of the humoral antibodyresponse
B cells and plasma cells secrete immunoglobulins,
which protect the host by various methods, includ-
ing preventing bacterial adherence, inactivating bac-
terial toxins and by acting as opsonins for phago-
cytosis by polymorphonuclear neutrophils. Poly-
clonal B-cell responses have been cited as being
important in the pathogenesis of the progressive
periodontal lesion (306) and it is generally agreed
that polyclonally induced immunoglobulin produc-
tion in humans is regulated by T cells (27,2621.How-
ever, the question of whether antibodies produced
in response to periodontal pathogens are protective
or not is still controversial.
B cells produce IL-1, which acts as a co-stimu-
latory signal for Th2 cells as well as mediating tissue
destruction via a number of pathways (233). If the
result of B-cell differentiation was protective anti-
body production, elimination of the causative organ-
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Cytokines and prostaglandins in periodontal disease
ism would ensue and disease progression would
stop. There is recent evidence to suggest that peri-
odontopathic organisms may not be part of the nor-
mal flora (106), hence, elimination of these organ-
isms would not only limit progression of the disease
(237) but may be a desirable outcome of the immuneresponse. Production of nonprotective antibodies in
susceptible subjects could, on the other hand, result
in continual connective tissue breakdown. Periods of
destruction would precede periods of stability and
the disease may have a cyclical pattern, with not all
B-cell lesions being destructive (104, 282).
The majority of T cells in the gingival tissues are
memory or primed cells (101,332),and a number of
studies have suggested the presence of peri-
odontopathic antigen-specific T and B cells in the
gingival tissues. Limit dilution analysis has demon-
strated the presence of T cells specific for I gingi-
valis and Actinomyces viscosus (the predominant or-
ganism found in the plaque of gingivitis subjects) in
the peripheral blood of gingivitis and periodontitis
patients (180). nitial treatment and the reduction in
plaque and hence antigen load resulted in a reduc-
tion in the frequency of I gingivulis- but not A.
viscosus-specific T cells in the adult periodontitis
subjects, although treatment resulted in a reduction
in both in gingivitis subjects. T-cell lines responsive
to I? gingivulis and E nucleutum have been shown to
be major histocompatibility complex class I1 re-
stricted and exhibit helper activity for B cells, as de-
termined by their ability to induce high levels of IgG
production in the presence of antigen (145).
Although direct evidence for the involvement of
antigen-specific T cells in chronic inflammatory
periodontal disease in humans has still not been
demonstrated, use of an animal model has shown
that cells of an Actinobacillus actinomycetemcomit-
uns-specific T-cell clone A3 adoptively transferred
into normal Rowett rats resulted in increased IgG
and IgM serum antibodies to A. actinomycetem-
comituns and reduced periodontal bone loss after in-fection (331).Athymic recipients showed no signifi-
cant antibody production or protection from bone
loss. When A3 clone T cells were adoptively trans-
ferred together with naive lymph node T cells from
normal rats into A . actinomycetemcomituns-infected
athymic animals, there was a significant increase in
specific serum antibody levels as well as in vitro pro-
liferation of spleen lymphocytes to antigen com-
pared with nude animals receiving lymph node T
cells alone (72). These authors suggested the lymph
node T cells have enabled survival of the A3 cells in
the athymic mice. These studies have demonstrated
that specific antibody can be protective in peri-
odontal disease, further supporting the concept of
local antigen-specific immune responses.
Protection has been demonstrated in a number of
studies. Serum from patients with severe peri-
odontitis containing high titers of anti-I? gingivulisantibodies completely inhibited in vitro bone re-
sorption, whereas serum from patients with low tit-
ers failed to inhibit this bone resorption, indicating a
possible protective role for specific antibodies (194).
Immunization of a 43-kDa fimbrial protein provided
protection against periodontal tissue destruction
when tested in I gingivulis-infected gnotobiotic rats
(871, and Kesavalu et al. (154) demonstrated that in
animals immunized w i t h I? gingivalis, the resulting
antibodies elicited gave a measure of protection by
functioning primarily as opsonins resulting in
phagocytic destruction of virulence components.
Complement-mediated killing of I gingivulis by hu-
man serum also appeared to depend on the pres-
ence of high levels of specific antibody in sera from
periodontally healthy patients, and those with adult
periodontitis containing low levels had little bacteri-
cidal activity (228).
However, not all anti-I? gingivulis antibodies are
protective (321). Schenk (272) reported significantly
greater levels of IgG and IgA antibody against I gin-
givulis lipopolysaccharide in periodontitis subjects
than controls with a healthy periodontium, and Ke-
savalu et al. (154) found that immunization with
whole cells or lipopolysaccharide of P gingivalis pro-
vided no protection against the lethal effects after
challenge with lipopolysaccharide. Chen et al. (36)
also demonstrated that immunization of mice with I
gingivulis lipopolysaccharide did not result in readily
detectable IgG or IgM levels to lipopolysaccharide,
nor did it reduce the severity of P gingivulis infec-
tion. Taken together, these results suggest that re-
sponses to lipopolysaccharide do not induce a pro-
tective response and that a response to these anti-
gens may not prevent progression of disease.Lipopolysaccharideand other carbohydrate antigens
tend to stimulate IgG2 rather than IgGl or IgG3,
which are generally produced in response to protein
antigens (226, 273). A predominance of serum IgG2
antibodies that lack strong complement fixation and
opsonic properties have been reported in peri-
odontal disease subjects, so that the humoral re-
sponse to I? gingivufis may be ineffective in clearing
this organism (176, 321). A nonprotective immune
response is also suggested by studies demonstrating
the presence of low-avidity anti-I? gingivalis anti-
bodies, which may be incapable of effectively medi-
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Gemrnell et al.
Fig. 6.Tumor necrosis factor a (TNF-a) and IL-1 mediate
adhesion molecule expression on endothelid cells and
hence play a role in the migration of polymorphonuclear
neutrophils (PMNs), lymphocytes and macrophages MQ)into the periodontal tissues
ating a variety of immune responses (176, 3211, and
the general inability to demonstrate immune com-
plexes in the gingival sulcus (37, 105, 2411, support-
ing the notion that there is a compromised ability to
eliminate or reduce the numbers of microorganisms
and their products from the gingival sulcus (176).
Macrophages and dendritic cells both bind anti-
gen by relatively nonspecific mechanisms. The exist-
ence of different antigen-presenting cells raises the
question about differences in their roles in the acti-
vation of T cells. Macrophages and dendritic cells
may provide signals that initially activate T cells,
while B-cell presentation then allows for further acti-
vation and clonal expansion of these already acti-
vated cells. Evidence that B cells direct Th2 CD4+
T cells whereas macrophages activate Thl cells (20)
provides support for antigen-specific T- and B-cell
activation leading to Th2 responses in the B-cell
periodontitis lesion. It is of interest that the A3 cells
used in the above studies were Th2 cells, and
Eastcott et al. (72) have suggested that Th2 cells are
protective in periodontal disease and Thl cells are
destructive. Ebersole Taubman (74) speculate that
Th2 cells produce IL-4 and IL-5, which are essential
for B-cell production of antibody. Even though the
Th2 A3 antigen-specific cells induced protective
antibody, the cytokine profiles of antigen-specific T
cells in the periodontal lesion in humans and their
relationship to protective and nonprotective anti-
bodies have yet to be determined.
Cytokines in tissue destruction
IL-1 is a principal mediator of inflammatory re-
sponses acting on many cell types and is itself pro-
duced by many different cells, including macro-
phages, endothelial cells, B cells, fibroblasts, epi-
thelial cells, astrocytes and osteoblasts in response
to microorganisms, bacterial toxins, complement
components or tissue injury (60). One of the most
important actions of IL-1 is its induction of othercytokines (224), and it appears to be part of a net-
work of cytokines with self-regulating and self-sup-
pressing properties (108). IL-6 is produced by both
hemopoietic and nonhemopoietic cells and induces
immunoglobulin secretion in both preactivated mu-
rine and human B cells and therefore induces the
final maturation of B cells into high-rate immuno-
globulin-secreting cells (224). Like IL-1, it appears to
have a major role in the mediation of inflammatory
and immune responses initiated by infection or in-
jury. Tumor necrosis factor is also a multipotential
cytokine having a wide variety of biological effects
and has been suggested to have similar effects as IL-
1 (170). Tumor necrosis factor a is produced mainly
by macrophages in response to agents such as lipo-
polysaccharide (38). Both tumor necrosis factor a
and IL-1 have been shown to act on endothelial cells
to increase the attachment of polymorphonuclear
neutrophils and monocytes and thus help to recruit
these cells into sites of inflammation (16) (Fig. 61.
IL-1 and tumor necrosis factor a are key mediators
of chronic inflammatory diseases and have the poten-
tial to initiate tissue destruction and bone loss in peri-
odontal disease (18). L-1 has been shown to stimulate
fibroblasts in culture to produce collagenase (253).
Tumor necrosis factor also mediates tissue destruc-
tion by stimulating collagenase (50) and degradation
of type 1collagen by fibroblasts leading to connective
tissue destruction (196). IL-1 is the most potent
known inducer of bone demineralization (Fig. 7) and
synergizes with tumor necrosis factor a n stimulating
bone resorption (292) as well as major changes in the
connective tissue matrix (246). On its own, tumor ne-
crosis factor is one hundred fold less potent than IL-1
Fig. 7. 1L-1produced by macrophages ( M 0 ) as the major
mediator of tissue breakdown in periodontal disease
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Cvtokines and mostanlandins in periodontal disease
in bone resorption assays (292). Tumor necrosis factor
molecules stimulate bone resorption by inducing the
proliferation and differentiation of osteoclast pro-
genitors and activating formed osteoclasts indirectly
(15,210,307).L-6 lso appears to have a role in bone
resorption. This cytokine was first found to stimulate
the formation of multinucleated cells with features
similar to osteoclasts (195) nd has now been shown
to be a potent stimulator of osteoclast differentiation
and bone resorption (259) and inhibitor of bone for-
mation (141).
Destructive cytokines in periodontal disease
IL- levels have been shown to be elevated in the gin-
giva of adult periodontitis subjects compared with
clinically healthy or gingivitis-affected individuals
(136, 08) and from active periodontitis sites versus
inflamed stable sites (293). urthermore, IL-1 evels
decrease after periodontal treatment (188, 91). IL-6
has also been shown to be increased in the gingival
crevicular fluid of patients with refractory peri-
odontitis (251),and IL-6message has been detected
in inflamed gingival tissues but not al l healthy tissues
examined (298). n the latter study,IL-6 rotein could
only be demonstrated in the inflamed tissues. Neither
of these studies correlated bone or connective tissue
destruction directly with IL-6evels.
As well as demonstrating the presence of IL-1-j3n
all gingival crevicular fluid samples collected fromsevere periodontal breakdown, tumor necrosis factor
a was also detected although in only about half the
samples and at only about 10% of the concentration
of IL-1-p 335).Another study also showed tumor ne-
crosis factor a o be present at very low or undetect-
able levels in gingival crevicular fluid (2631, nd Mat-
suki et al. (190)demonstrated that tumor necrosis
factor was produced by macrophages in inflamed
gingiva. Activated macrophages are also a well estab-
lished source of IL-1-p roducing up to ten times
more IL-1-pmessenger RNA than IL-1-a essengerRNA (59, 184). Matsuki et al. (191) howed defini-
tively using combined immunohistochemistry and
in situ hybridization that the IL-1messenger RNA-
expressing cells in human inflamed gingiva were
macrophages. The rate of IL-1messenger RNA was
higher in the connective tissue furthest from the
pocket epithelium, suggesting a role in the alveolar
bone resorption that occurs in periodontal disease.
This is supported by a study demonstrating that ad-
ministration of IL-1-p ccelerated alveolar bone de-
struction in ligature-induced periodontal tissue in-
flammation in rats over a 2-week period (162).
Human gingival fibroblasts may also contribute
significant levels of certain inflammatory cytokines
in the gingival tissues (67).Formalin-killed prepara-
tions of two possible periodontal pathogens, A. acti-
nornyceterncomitans and Carnpylobacter rectus have
been shown to stimulate IL-6 nd IL-8productionby human gingival fibroblasts although IL-1-pwas
suppressed during the initial 3- o 12-hour period.
Reddi et al. (250) also showed that surface-associ-
ated material ( S A M ) rom a number of oral patho-
gens including A. actinornycetemcornitans Eikenella
corrodens, I gingivalis, C . rectusand Prevotella inter-
media induced IL-6 ut not IL-1-f3 r tumor necrosis
factor a from gingival fibroblasts, although all three
cytokines were induced from peripheral blood
mononuclear cells. A. actinornyceterncomitans E.
corrodens and I gingivalis were the most potent in-
ducers, especially A. actinornyceterncomitans which
has also been shown to have bone-resorbing activity
(325).Gingival fibroblasts may therefore be able to
contribute to periodontal tissue inflammation (67).
Hendley et al. (134) uggested that oral polymor-
phonuclear neutrophils may be an important source
of IL-1-p n periodontal disease, as the amount pro-
duced by these cells was strikingly greater than that
produced by circulating polymorphonuclear neutro-
phils activated in vitro. Keratinocytes which have
been demonstrated to produce IL-1-a 164), ould
also be a source of IL-1 n the gingival tissues, al-
though Matsuki et al. (191)could not detect IL-1
messenger RNA or protein in the epithelium of peri-
odontal disease subjects.
Whether B cells contribute to IL-1 n inflamed gin-
gival tissues has not yet been demonstrated. How-
ever, Ito et al. (146)have shown that lipopolysac-
charide from I gingivalis, I? intermedia and A. acti-
nornyceterncomitans increased the numbers of
osteoclast-like cells in lipopolysaccharide-respon-
sive C3HIHeN bone marrow cells in culture. They
concluded that lipopolysaccharide from gram-nega-
tive bacteria in periodontal pockets may induce os-teoclastic differentiation and promote alveolar bone
loss in periodontal disease. The method of action of
this increased osteoclast differentiation and any in-
volvement of cytokines produced by lipopolysac-
charide-induced polyclonal B-cell activation were
not determined.
Inhibitors of destructive cytokines
The IL-lra is a member of the IL-1gene family that
binds IL-1 eceptors without inducing apparent cell
activation. It is produced by monocytes 6)and poly-
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Gemmell et al.
morphonuclear neutrophils (249), and an intracellu-
lar variant is produced by keratinocytes (17). Tumor
necrosis factor a has been reported to induce both
intracellular IL-lra and IL-1-a by keratinocytes, and
the ratio of these two cytokines may influence the
inflammatory profile in the epidermis (165). It is un-
clear whether the IL-lra actually acts as an antagon-
ist in uivo as high levels of IL-lra have been reported
(215) at sites of chronic inflammation such as the
synovium of patients with rheumatoid arthritis.
However, increasing mucosal inflammation in in-
flammatory bowel disease in children has been
shown to be associated with a decrease in the effec-
tive IL-1ra:IL-1-f3 atio in which IL-lra normally pre-
dominates (142). Dinarello (61) has also reported
that, due to the ability of IL-lra to block IL-1 recep-
tors without agonist activities, the severity of several
diseases such as septic shock, inflammatory bowel
disease and experimental arthritis has been reduced.
In support of this, Norman et al. (218) showed that
tumor necrosis factor a and IL-6 are elevated and
correlate well with the severity of local pancreatic
destruction during experimental acute pancreatitis
in mice. Administration of IL-lra before or after the
induction of pancreatitis significantly attenuated the
rise of these cytokines and was associated with de-
creased severity of pancreatitis and reduced intrinsic
pancreatic damage. The use of IL-lra has also been
shown to delay the onset and reduce the severity of
paralysis and shorten the duration of disease in anexperimental allergic encephalitis, an animal model
of multiple sclerosis (1871, and treatment of rabbits
with experimentally induced acute colitis with IL-lra
markedly reduced the severity of inflammation and
necrosis of the colon (45). High levels of IL-lra have
also been measured in the gingival crevicular fluid
of patients with adult periodontitis (140) although
the relevance to disease has not been determined.
Furthermore, P388D1 murine macrophages have
been shown to produce an IL-1 inhibitor identical to
the IL-lra after stimulation with A. acrinomycerern-cornitans lipopolysaccharide, which may play an im-
portant mediatory role in the development of peri-
odontal disease (217).
Soluble cytokine receptors reduce the biological
effects of cytokines by decreasing the concentration
of surface receptors and by binding free cytokine
and consequently reducing the concentration of sol-
uble cytokine and therefore the biological effects of
cytokines (140). There are two IL-1 receptors, type 1
and 11. While type receptors signal, type I1 can bind
IL-1 but will not transduce a signal. w e 1 receptors
arc cleaved and shed and in the plasma will bind IL-
~ ~ ~~~ ~
1-p but not IL-lra (297). Therefore there is no com-
petition between the soluble receptor and the recep-
tor antagonist (140). Tumor necrosis factor a L-1
and lipopolysaccharide have been shown to induce
soluble tumor necrosis factor a receptors by mono-
cytes (135). Increased soluble tumor necrosis factor
a eceptors have been found in the sera and synovial
fluids of patients with rheumatoid arthritis (46), and
high levels of both the p55 and p75 tumor necrosis
factor a receptors have been demonstrated in gingi-
val crevicular fluid from periodontal disease sites
(140).
Several cytokines have been implicated in the sup-
pression of tissue destructive cytokines. IL-10 has
been shown to downregulate IL-I and tumor ne-
crosis factor a gene expression in human monocytes
(86) and polymorphonuclear neutrophils (30, 31).
Further, IL-10-deficient mice suffer from chronic en-
terocolitis similar to human inflammatory bowel dis-
ease, which is characterized by the infiltration of
neutrophils and mononuclear cells (242) and is as-
sociated with increased tissue levels of tumor ne-
crosis factor, IL-1, IL-6 and IL-8 (62). IL-10 has been
demonstrated to down-regulate IL-1-f3 and tumor
necrosis factor a secretion as well as messenger RNA
levels in peripheral monocytes and mononuclear
cells from the lamina propria of patients with in-
flammatory bowel disease. At the same time, IL-lra
secretion was induced and IL-10 was able to restore
diminished in uitro IL-1ra:IL-1-P ratios to normal
levels. In uivo topical application of IL-10 to patients
with ulcerative colitis resulted in the down-regula-
tion of proinflammatory cytokine secretion both loc-
ally and systemically (274).
IL-4, like IL-10, has been shown to downregulate
IL-1 and tumor necrosis factor a gene expression in
human monocytes (86) and to inhibit their secretion
and that of another proinflammatory cytokine, IL-6
(305). Furthermore, IL-4 has been shown to induce
the death by apoptosis of IL-1- or Iipopolysacchar-
ide-stimulated monocytes, but not unstimulatedmonocytes (182). Human monocytes contribute to
both the persistence and resolution of chronic in-
flammation, and the regulation of the production of
monocyte mediators may have great value in healing
or in reducing the immunopathogenesis of chronic
inflammation (181).
Transforming growth factor p is an anti-inflam-
matory agent (239). It is produced locally at the site
of resorption of bone and has been shown to initiate
new bone formation (32). Transforming growth fac-
tor p appears to be an IL-1 inhibitor and acts by re-
ducing the constitutive or induced level of IL-1 re-
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Cytokines and prostaglandins in periodontal disease
ceptors (70). Gemmell Seymour (103) demon-
strated that more transforming growth factor p may
have been produced by peripheral blood mono-
nuclear cells in culture in the absence of stimulatory
bacteria, confirming another study which showed
that without specific bacterial stimulation, the pre-dominant product by peripheral blood adherent
cells was inhibitory (319). Furthermore, Winning et
al. (326) demonstrated the absence of a factor of ap-
proximately the same molecular weight as the IL-lra
in supernatants of periodontal diseased epithelial
cells, which was consistently found in healthy epi-
thelial cell supernatants. Hammerberg et al. (124)
have suggested the presence of an IL-lra isolated
from sections of skin by polymerase chain reaction
analysis could possibly have been derived from Lan-
gerhans cells. Howells (140) states that destructive
periodontal disease may be due to insufficient levels
of inhibitors rather than increased levels of IL-1 and
tumor necrosis factor a.The mechanisms of interac-
tions of cytokines in periodontal disease need to be
elucidated to be able to use cytokine inhibitors clin-
ically to the best advantage.
IL-8 is produced by a wide variety of cell types
including polymorphonuclear neutrophils, mono-
cytes and macrophages, fibroblasts and keratino-
cytes in response to microorganisms, mitogens and
endogenous mediators such as IL-1 and tumor ne-
crosis factor. IL-8 has been implicated as a major
participant in a number of diseases, including rheu-
matoid arthritis in which increased levels correlated
with increased polymorphonuclear neutrophils
numbers in collected synovial fluid samples (161).
Studies have shown that lipopolysaccharide-stimu-
lated polymorphonuclear neutrophils release IL-8 as
well as IL-1-p and tumor necrosis factor a,which
both independently can induce IL-8 secretion them-
selves (29). lipopolysaccharide-stimulated polymor-
phonuclear neutrophils also secrete IL-lra, which re-
sults in the blocking of IL-8 synthesis in monocytes
(117) and IL-8 release in polymorphonuclear neutro-phils (29). One of the major functions of IL-8 is its
ability to induce the directional migration of cells,
including polymorphonuclear neutrophils, mono-
cytes and T cells (229), thus playing a key role in the
accumulation of leukocytes at sites of inflammation
(215).As the primary effector cells in acute inflam-
mation, human polymorphonuclear neutrophils
synthesize and release inflammatory cytokines and
thereby modulate both T- and B-cell function (174).
Production of IL-8 by polymorphonuclear neutro-
phils suggests that having arrived at the site of in-
flammation, these cells promote the further recruit-
ment of polymorphonuclear neutrophils and the ac-
cumulation and activation of monocytes and
macrophages and lymphocytes (29).
Polymorphonuclear neutrophils are terminally
differentiated short-lived cells so that their ability to
produce cytokines may be regarded as havinglimited physiological significance (29). However,
polymorphonuclear neutrophils survival can be ex-
tended by exposure to signals such as lipopolysac-
charide and the cytokinesIL-1-p, tumor necrosis fac-
tor a, L-6, IFN-y and certain colony-stimulating fac-
tors 24, 44). Polymorphonuclear neutrophils are
found not only within the sulcular and junctional
epithelium and within the underlying connective
tissue (9, 2751, but also comprise over 90 of the
leukocytes in gingival fluid (8). IL-8 has been de-
tected in the gingival crevicular fluid of adult peri-
odontitis patients (2351, and cytokine message has
been identified in both healthy and diseased peri-
odontal tissues (309). Furthermore, IL-8 message has
been shown to be restricted to the junctional and
sulcular epithelium in close proximity to infecting
organisms, and this was consistent with the localiz-
ation of polymorphonuclear neutrophils in the same
area, suggesting a role for IL-8 in the selective re-
cruitment of polymorphonuclear neutrophils to-
wards the infecting plaque bacteria (310).
Both protective and destructive influences of
polymorphonuclear neutrophils have been sug-
gested such that their role in adult periodontal dis-
ease is still controversial. Much of the evidence
suggesting a protective function comes from the ob-
servation that patients with systemic polymorpho-
nuclear neutrophils defects such as neutropenia, ag-
ranulocytosis and Chkdiak-Higashi syndrome also
display an increased severity in periodontal break-
down (313). However, bacteria and bacterial prod-
ucts are capable of evading polymorphonuclear neu-
trophils using a number of mechanisms. Some peri-
odontal bacteria such as I gingivalis, A.
actinomycetemcomitans and E nucleaturn have beenshown to inhibit some of the protective functions of
polymorphonuclear neutrophils such as phago-
cytosis, chemotaxis, production of superoxide dis-
mutase and direct leukocytotoxicity (2,288). MacFar-
lane et al. (179) reported significantly impaired
phagocytosis due to a decreased rate of adhesion
and opsonization by polymorphonuclear neutro-
phils from patients with refractory periodontitis
compared with healthy patients, suggesting a strong
association between polymorphonuclear neutrophil
defects and refractory disease. Bacteria, including I
gingivalis, produce proteases that can cleave com-
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Gemmell et al.
plement and immunoglobulins preventing opsoniz-
ation and subsequent polymorphonuclear neutro-
phi1 killing of invading bacteria (314).Yamazaki et al.
(334) have shown that peripheral blood polymor-
phonuclear neutrophils stimulated with a range of
periodontopathic bacteria did not produce IL- 1 butrather an IL-1 inhibitor. In contrast, a nonoral micro-
organism did induce IL- 1 secretion. The results sug-
gested a mechanism whereby periodontopathic bac-
teria could evade the protective effects of polymor-
phonuclear neutrophils and also indicated a
regulatory role for these cells in periodontal disease.
Prostaglandins and prostaglandin inhibitors
Cytokines exert their effect by first binding with spe-
cific receptors that, in turn, bind to second messages
so that a signal is delivered inside the cell in re-
sponse to the cytokine ligand (47). One group of sec-
ond messengers is derived from hydrolysis of mem-
brane phospholipids. Phospholipase A, cleaves its
substrate to generate arachidonic acid, a precursor
of a group of small lipids known collectively as eicos-
anoids, which act as inflammatory agents (173).Ara-
chidonic acid is degraded via one of two pathways.
The action of lipoxygenases (a group of additional
oxidative enzymes) results in the formation of the
hydroxyeicosatetraenoic acids and leukotrienes. Al-
ternatively, prostaglandin endoperoxide synthases
(cyclooxygenase) catalyze the conversion of arachi-
donic acid into the prostanoids (prostaglandins and
prostacyclins) and thromboxanes (128).
Prostaglandins are comprised of 10 classes, of
which D, E, E G, H and I are the most important
biologically (128). The existence of the prosta-
glandins has been known for many years, but their
role in inflammation was only revealed in the 1960s
(139). Evidence that prostaglandins could mediate
bone resorption was first reported in 1970 (156, 247)
and a role for prostaglandins in periodontal bone
loss soon followed (111, 112).Early work established
prostaglandin E, as the most potent stimulator of
bone resorption (58, 115),and subsequent studies in
periodontal disease have tended to concentrate on
this particular prostaglandin (76, 219). Prostaglandin
E, exhibits a broad range of proinflammatory effects.
It contributes to the flare and weal effects by in-
ducing vasodilation and increasing capillary per-
meability, and these effects are enhanced by syner-
gism with other inflammatory mediators (323). IL-1
and tumor necrosis factor activate the arachidonic
acid pathway, and a number of their effects can be
attributed to prostaglandin E2 (38).
Increased production of the eicosanoids is associ-
ated with inflammatory reactions (38)and one treat-
ment of inflammation has been directed towards the
enzymes which release these products. Cyclooxygen-
ase (COX) was isolated in 1976 (2001, but its wide
distribution fails to explain the differing prostanoidproductions seen across differing tissues. Recently, a
second form of cyclooxygenase (now designated
COX-2) was isolated (163, 287). COX-2 expression is
inducible in response to a number of stimuli includ-
ing lipopolysaccharide (172, 232) and many cyto-
kines such as IL-1, tumor necrosis factor and trans-
forming growth factor a (71, 107, 149). While both
COX-1 and COX-2 catalyze the same reaction, at
resting conditions COX-2 is mostly undetectable
(278). Recently, a third isoform (COX-31, possibly in
the brain, has been speculated (315). With the dis-
covery of COX-2, there has been a renewed interest
in the development of drugs to block the action of
cyclooxygenase.
Corticosteroids have long been used to control in-
flammation. The specific action of the cortico-
steroids on phospholipase A2 has recently been de-
duced. The action appears to be indirect, causing the
release of lipocortin, an inhibitory protein, from
some cells (318).Alternatively, cytoplasmic glucocor-
ticoid receptors may also be activated. These recep-
tors regulate transcription of some primary response
genes, including those responsible for COX-2 (94).
This same receptor complex is also responsible for
inhibiting transcription of some cytokines including
IL-1 and tumor necrosis factor a (13). The conven-
tional anti-inflammatory drugs have been retrospec-
tively examined to determine their COX-1 and -2 sel-
ectivity and these, along with more recent drugs, are
shown in Table 2.
As inflammatory cytokines have the ability to up-
regulate COX-2, inhibition of these cytokines may
represent another area of COX-2 control. Radicicol is
a fungal antibiotic thought to act as a protein tyro-
sine kinase inhibitor and has been shown to inhibit
the expression of COX-2 in lipopolysaccharide-
stimulated macrophages without effecting enzy-
matic activity (35). A new family of drugs, the cyto-
kine-suppressing anti-inflammatory drugs, has been
described (1 91, of which SKF 86002 is the prototype
(2361,These drugs are potent and selective inhibitors
of one of the mitogen-activated protein kinase fam-
ily termed alternatively RK, p38 or cytokine-sup-
pressing anti-inflammatory drugs-binding protein.
These protein kinases are thought to act as signal
transducers when activated by physicochemical
stress, lipopolysaccharide or pro-inflammatory cyto-
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Cvtokines and m ostanlandins in veriodontal disease
Table 2. Selective inhibition of cyclooxygenase
by nonsteroidal anti-inflammatory drugs
DIUE cox-1 cox-2
Aspirin (167)Indornethacin (163)
Piroxicam (167)Naproxen (167)Tenidap* I2311
Ibuprofen (167)
Nabumetone (289)
Etodolac (167)Nimesulide (R-805) 14)
Hosulide (CGP 8238) (157)
Meloxicam (65.841
NS-398 (109)
L-745,337 (23, 33)
sc 58125 (35, i44)T-614b I35,302)
I
BF-389 (199)
Also nhibits monocyte interleukin l p production (37, 100).
Also inhibits monocyte interleukin 18 and interleukin 6 production (49,301).
kines such as IL-1 and tumor necrosis factor (171).
Activation is required for production of IL-1 and tu-
mor necrosis factor and probably prostaglandins, as
cytokine-suppressing anti-inflammatory drugs have
been shown to inhibit strongly the production of
COX-2 in response to IL-1 (120).
The use and complete understanding of COX-2 in-
hibitors is still in its infancy, however it seems likely
that in the future, various drugs either blocking the
enzyme or inhibiting its production will come to be
used as important modulators of inflammation.
Prostaglandins in periodontal disease
In vitro studies of the effect of prostaglandins on
periodontal tissues have concentrated on two ap-
proaches: studies of the production and effects of
prostaglandins per se and studies of the effect of
drugs to inhibit Prostaglandins. Early studies showed
the possibilities for bone resorption from gingival
fragments, and indomethacin was used to elucidatea role for prostaglandins (111, 112, 114).The produc-
tion of prostaglandins from gingival tissue increases
with inflammation and is further increased by estro-
gens and progesterones (75). Human monocytes
have also been shown to produce prostaglandin E2
when stimulated with lipopolysaccharide from puta-
tive periodontal pathogens (99). lnflamed gingival
samples synthesize significantly larger amounts of
prostaglandins when incubated with arachidonic
acid than do healthy gingival samples (197). Al-
though most work has concentrated on prosta-
glandins, homogenates of inflamed gingiva metab-
olize most arachidonic acid via the lipoxygenase
rather than the cyclooxygenase pathway (77).Within
gingival lesions, prostaglandin E is mainly localized
within macrophage-like cells, suggesting a possible
immune regulatory role (175).
Resting monocytes from localized juvenile peri-odontitis patients have been shown to secrete sig-
nificantly more prostaglandin E2 than those from
control patients or severe generalized periodontitis
patients. Stimulation with lipopolysaccharide caused
a dose-dependent increase in prostaglandin E2 pro-
duction, which was significantly greater than that
shown by severe generalized periodontitis patients,
which was, in turn, significantly greater than that
found in controls (283). Recent work by the same
group indicated that the lipopolysaccharide hyper-
sensitivity of localized juvenile periodontitis mono-
cytes can be reversed depending on the age of the
cell cultures, highlighting some of the risks of in v i m
studies (284).
Both gingival and periodontal ligament fibroblasts
secrete prostaglandin E in response to IL-1-p and
also in response to media conditioned by lipopoly-
saccharide-stimulated monocytes (253). More recent
work has shown that periodontal ligament cells pro-
duce prostaglandin E even when unstimulated, but
this secretion is enhanced by incubation with IL-1,
IL -1 -B and tumor necrosis factora, nd the addition
of parathyroid hormone further enhances this effect
(267, 268). Incubation with combinations of these
cytokines and IFN-7 may have additive, synergistic,
subtractive, or suppressive effects on prostaglandin
E production by periodontal ligament fibroblasts
(266).
Cultivated gingival mononuclear cells from
chronic adult periodontitis patients produce elev-
ated IgG levels, which can be decreased by the ad-
dition of indomethacin. Prostaglandin E2 has a bi-
phasic action on these cells, whereby high doses de-
crease IgG levels but low doses increase them. When
combined with IL-4, ow doses of prostaglandin E2induce a synergistic rise in IgG production, sug-
gesting an immunoregulatory role for prostaglandin
E2 (127). Differing putative periodontal pathogens
appear to have differing activating abilities, and al-
though A. actinomycetemcomitans and Wolinella
recta both stimulate gingival fibroblasts to produce
IL-6 and IL-8, only W recta at high concentrations
causes an increase in prostaglandin E2 levels (67).
Various nonsteroidal anti-inflammatory drugs
have been used to further our understanding of the
role of prostaglandins and the possible effectiveness
of drugs in treating gingival inflammation (78). Of-
127
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Gemm ell et al.
fenbacher et al. (221) have developed an in uifro as-
say for testing the prostaglandin E2 production from
periodontal tissue homogenates and have been able
to test a range of nonsteroidal anti-inflammatory
drugs for their inhibitory effects. Similarly, rat bone
marrow stromal cell cultures have been used as abioassay for periodontal ligament fibroblast osteo-
genic inhibitory factors. All prostaglandins were
found to be inhibitory, although prostaglandin E,
and prostaglandin Fza were the most potent (227).
Gingival fibroblasts treated with prostaglandin E2
showed a significant concentration dependent inhi-
bition of D N A synthesis and could also reduce the
stimulation of DNA synthesis by IL-1-p and indo-
methacin (79). Both IL-1-p and tumor necrosis factor
a stimulated IL-6 production from gingival fibro-
blasts, but endogenous and exogenous prosta-
glandin E2 down-regulated this production at the
post-transcriptional level (300).
Conversely, triclosan (a nonionic antibacterial
compound) has been shown to inhibit the produc-
tion of prostaglandin E2 from IL- I-p-stimulated gin-
gival fibroblasts, possibly by inhibiting cyclooxygen-
ase (with a COX-1 preference) (97). It has been
shown that IL- 1 - p increases messenger RNA levels
for COX-2 but not COX-1 in gingival fibroblasts, and
this upregulation is prevented by dexamethasone
(an anti-inflammatory steroid) (336). Most prosta-
glandins have been shown to have an overall cata-
bolic effect on gingival fibroblasts, as evidenced by
their ability to alter cell morphology, suppress pro-
liferation and suppress DNA synthesis, collagen syn-
thesis and noncollagenous protein synthesis, al-
though there is no apparent effect on GAG synthesis
5).CyclosporineA, a common immunosuppressant
associated with gingival overgrowth, has a dose-de-
pendenr inhibitory effect on prostaglandin I, syn-
thesis in gingival tissues. As prostaglandin I nor-
mally exerts an anti-proliferative effect, i t has been
suggested that the lack of prostaglandin I? is respon-
sible for the gingival overgrowth associated with
cyclosporine A 214).
Animal studies. A hamster periodontitis model has
been used to show the inhibitory effects of indo-
methacin on bone resorption, suggesting that
prostaglandins may be in viuo uncouplers of bone
remodeling (265).Similar results with indomethacin
have been obtained in a squirrel monkey model and
even more inhibition of bone resorption was noted
with a topically applied nonsteroidal prostaglandin
synthetase inhibitor (316). Infusion of prostaglandin
E, over 3 weeks has been shown to have a dramatic
local osteogenic effect in dogs, although the long-
term stability of this new bone is unknown (185).
The dynamics of prostaglandin E2 production
have been followed in ligature-induced periodontitis
in rhesus monkeys. A 3-fold increase in the crevic-
ular fluid levels of prostaglandin E2 occurred after 3months, a 6 fold peak was found at 6 months with a
return to baseline levels after 12 months. The rise in
prostaglandin E2 levels correlated positively with the
clinical signs, which also plateaued at 6 months
(220). A similar rise was seen in beagles with nat-
urally occurring periodontal disease, and this in-
crease was significantly reduced by systemic ibup-
rofen, naproxen and topical flurbiprofen, further
emphasizing the role of the cyclooxygenase pathway
in periodontal bone loss (223) .In Wistar rats, the ap-
plication of prostaglandin E2 to the gingival sulcus
resulted in a dose-dependent increase in the number
of osteoclasts, although concentrations greater than
1.0 mglml were less effective (201).
By contrast, exogenous prostaglandin El adminis-
tered systemically to hamsters resulted in a marked
decrease in the number of osteoclasts, although their
intrinsic activity was enhanced and bone formation
was totally inhibited (26).In addition, near-by deliv-
ery of prostaglandin El in beagle mandibles has been
reported to result in the formation of cementum, al-
veolar bone and Periodontal ligament in 18 of 18 ex-
perimental sites compared with 1 of 7 control sites
(186).
Clinical studies. Assays for prostaglandins have
been performed on gingival tissues removed at
surgery. Prostaglandin E2 and thromboxane A2 were
detected only in inflamed tissues and while 6-K-
prostaglandin F1 was found in all tissues, lower
levels were detected in uninflamed gingivae (57).
Longitudinal monitoring of mean full-mouth crevic-
ular fluid prostaglandin E2 levels predicts well peri-
odontal attachment loss in the following 6 months.
Thus, as a screening test, the prostaglandin E2 levels
have a high degree of sensitivity (0.761, specificity
(0.96) and predictive value (0.92-0.95) at the patient
level but not necessarily at the site (222).
A double-blind clinical trial of the effects of
flurbiprofen on bone loss in a 6 month pre-treat-
ment period compared with the subsequent 2 years
(322) showed that the rate of bone loss in patients
talung the drug was significantly less than those re-
ceiving a placebo, although after 24 months there
was no difference between the bone loss rates of the
two groups. The authors speculated that the late loss
of this clinical effect could be due to a true loss re-
128
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Cytokines and prostaglandins in periodontal disease
lated to a switching to other bone resorptive path-
ways or simply to a decrease in patient compliance
after such a long period. The use of flurbiprofen has
also been assessed in resolving pre-existing gingival
inflammation. Systemic flurbiprofen alone reduced
significantly the Gingival Index scores and gingivalcrevicular fluid flow rates despite having no effect
on the amount of plaque, although there was little
additional benefit to be gained over toothbrushing
solely or in combination with the drug (132).
The experimental gingivitis model has also been
used to follow the changes in crevicular fluid prost-
anoid and cytokine levels in developing gingivitis.
Both IL-1-p and leukotriene B4 levels increased
rapidly but prostaglandin E2 and thromboxane B4
levels only increased in the fourth week, correspond-
ing to an increase in bleeding scores (130).This same
group used the model to examine the effect of
flurbiprofen on the prevention and treatment of gin-
givitis. The drug significantly inhibited the develop-
ment of redness and bleeding in the first 21 days
which were associated with a significant inhibition
of gingival crevicular fluid thromboxane B2 but not
prostaglandin E2.Over the following 7 days (21-28
days) the flurbiprofen continued to inhibit bleeding
but not redness, and this was associated with inhi-
bition of the significant rise in crevicular fluid
prostaglandin E2, hromboxane B2 and leukotriene
B4 seen in placebo control patients (131). A follow-
up study using systemic flurbiprofen (100 mglday)
with toothbrushing to resolve gingivitis showed no
difference in plaque and crevicular fluid flow after 7
days but greater resolution of inflammation in the
experimental group. Whether this difference was sig-
nificant clinically remains to be seen (133).A further
use of topical flurbiprofen (as a 1 w/w toothpaste)
has been tested over 12 months in patients treated
for chronic periodontal disease. Although there was
no significant difference between the treatment and
control groups in terms of clinical response, there
was a significantly greater proportion of sites show-ing bone gain (8%) compared with the placebo
group (3.3%) 129).
The association of prostaglandins with increasing
inflammation has proved difficult to characterize.
While increasing levels are seen from health to gingi-
vitis to periodontitis (2121, healthy sites in patients
with periodontitis experience also have higher levels
of prostaglandin E, although levels are lower in
maintenance patients than in patients with ongoing
periodontitis. Thus individual site levels of prosta-
glandins are difficult to reconcile with the clinical
appearance of the site in isolation (73).
Cytokine therapy
As mentioned earlier, many diseases are due to inap-
propriate cytokine activity; hence, the use of cyto-
kines to change the course of the disease or to allevi-
ate symptoms or side effects of other therapies is be-coming important in clinical medicine (38).
Cytokines can theoretically be used as therapeutic
modalities in two forms. As already mentioned, over-
production of cytokines may be inhibited by the
cytokine-suppressing anti-inflammatory drugs. Al-
ternatively, missing, defective or reduced cytokines
andlor their receptors can be replaced directly to re-
constitute a reduced immune system or used to
stimulate further the immune system in cases of
overwhelming infection or neoplasias. These therap-
ies can be achieved using recombinant cytokines or
genes encoding for them.
Cytokine therapy is initially very attractive; how-
ever, a number of clinical problems have arisen that
complicate the reality. The initial attraction for cyto-
kine therapy was in hematopoiesis. Following cyto-
toxic chemotherapy, bone marrow transplants and in
conditions such as aplastic anemia, neutrophil dys-
functions and agranulocytosis, there is a need for
rapid growth of normal cells (203). Early work with
pancytopenic monkeys (66) and patients recovering
from autologous bone marrow transplant (216)
showed that injection of recombinant human granul-
ocyte-macrophage colony-stimulating factor resulted
in a rapid increase in neutrophils. This increase was
dose-dependent, and could be maintained for up to a
month without significant side effects as long as the
infusion continued. Cessation of therapy resulted in
the return to normal cell levels in 3-7 days.
In the treatment of tumors, early work began with
the recognition that incubation of leukocytes with
IL-2 resulted in a cytotoxic cell capable of killing tu-
mor cells (118). Clinical trials of this technique in
humans using ex uivo incubated leukocytesw i th co-
administration of IL-2 resulted in significant tumorregression but were also associated with systemic
fluid retention due to leaky capillaries. This effect
was probably due to induction of other cytokines
and limits the dose that can be administered. Renal
cell carcinoma and melanoma appear to be most
susceptible to this form of therapy (261). Systemic
IFN-a nd locally administered tumor necrosis fac-
tor have also been used successfully in clinical trials.
In the future it may be ideal to combine cytokines to
increase their therapeutic effects, as has been done
with IL-3 and granulocyte-macrophage colony-
stimulating factor.
129
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Gemmell et al.
In infectious diseases, IFN-y and IL-2 can be used
to some effect in the treatment of lepromatous lep-
rosy (213) and cutaneous leishmaniasis (921, due
most likely to an alteration in the ThllTh2 balance
(270).This fine balance has been studied in a murine
model of Schistosoma infection in which excessiveamounts of IL- 10 suppress IFN-7 production. Treat-
ment with anti-IL-10 antibodies in this model may
represent a correction in the balance of the anti-Thl
activities of IL-10 and the anti-Th2 effects of IFN-y
(285). Conversely, IL-10 may be useful in the treat-
ment of Thl-mediated diseases such as contact der-
matitis and possibly psoriasis 7).
Recombinant cytokines and or their inhibitors can
be used in the control of rheumatoid arthritis. A
number of short term clinical trials have been
undertaken using a variety of cytokine-blocking
mechanisms. Tumor necrosis factora, n importantmediator in arthritis, can be blocked by the use of
cA2, a chimeric (human/mouse) neutralizing anti-
tumor necrosis factor monoclonal antibody (158).
double-blind study of cA2 indicated a significant im-
provement as measured by a number of parameters
of disease (81) nd this effect continued even with
repeated administration (82). Other positive results
have been reported with CDP571 (a humanlmouse
anti-tumor necrosis factor a monoclonal antibody)
(248) and a sTNFR:Fc fusion protein (twosoluble tu-
mor necrosis factor receptor molecules fused to the
Fc portion of human IgG1) (204). The use of a re-
combinant human IL-1 receptor has also been tried
for the treatment of rheumatoid arthritis. Early re-
sults were promising but later trials have noted sig-
nificant side effects and questionable benefit (69).
Other positive results have been reported with an
anti-IL-6 monoclonal antibody (B-E8) (320).
In different clinical situations, cytokines, combi-
nations of cytokines, antibodies to cytokines, soluble
receptors for cytokines and agonists could all be po-
tentially used for treatment. Two major problems re-
main to be overcome. One is the need to achieve the
cytokine levels or blockade in the long term, and the
second is to overcome the adverse outcomes that
may result from systemically blocking or increasing
cytokines that are normally involved in homeostasis
(80).Any cytokine treatment for periodontal disease
probably needs to address these problems.
Gene therapy
Over the last decade, advances in the understanding
of the molecular basis of diseases have led to a much
Fig. 8. Principles of gene therapy. Ag: antigen.
greater understanding of disease processes, which in
turn has led to the concept of gene therapy. The pri-mary aim of gene therapy is to treat disease states
through gene insertion strategies to correct genetic
defects in somatic cells (126). It can be viewed as
using DNA as a drug, either to correct a defect, en-
hance a response or mark a foreign cell for sub-
sequent eradication. Gene modification can occur ex
uiuo or in uivo and can involve either normal or ab-
normal cells. Problems have arisen for long-term
changes, as there is a need to alter early precurser
cells and often these cells are not dividing, or in-
serted genes may not remain transcriptionally active.
The procedure of altering the genornic contents of
the cell requires the use of a vector to carry and in-
sert the new genetic material (Fig. 8). Methods that
have received approval to date include retroviruses,
adenoviruses, liposomes and direct DNA injection.
Retroviruses can only incorporate smaller genes
(maximum 7 kb) due to their relatively small genome
(19).These viruses contain single-stranded RNA, and
once in the host cell, the viral RNA must undergo
reverse transcription to double-stranded DNA which
is then incorporated into the host cell genome. This
property of most retroviruses means that integration
only occurs in dividing cells. Because most tissues in
adults consist of nondividing cells, these vectors are
usually applied ex uiuo and in humans have been
used to transfect autologous T cells (3) and bone
marrow cells (137) with the adenosine deaminase
gene, which is deficient in severe combined im-
munodeficiency disease and liver cells with the low-
density lipoprotein receptor gene (121). Adeno-
viruses usually result in mild diseases in humans
but, in contrast to retroviruses, these contain double
stranded DNA and do not require host cell division
for replication. The viral genome is much larger
130
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Cytokines and prostagland ins in periodontal disease~ ~~
(about 35 kb) and more complex than that of retro-
viruses. Adenovirus vectors have been used in
humans in the treatment of cystic fibrosis 48);how-
ever, because adenoviruses do not integrate into di-
viding cells, their therapeutic effect may be transi-
ent, requiring repeated administration, but this maybe limited by the immunogenic effects of the wild-
type adenoviruses. Adeno-associated viruses contain
single linear strands of DNA and require simul-
taneous infection of the host cell with adenovirus or
certain other viruses in order to replicate. The main
problem for use as a vector appears to be that the
introduced DNA cannot be very big (less than 5 kb)
and currently is difficult to produce in large quan-
tities.
Viral vectors have been modified such that they
cannot produce systemic infections but retain the
ability to be incorporated into the cell. For the gene
insertion therapy to work, 1) the gene must be in-
serted into a large number of cells; 2) the new gene
must be persistently active;3) the gene product must
be compatible with the biology of the target cell to
cause the therapeutic effect (particularly with re-
spect to humoral and cellular immunity);and 4) The
vector titers need to be high enough to increase the
chances of the new DNA being incorporated into the
rare target cell that is dividing (in the case of retro-
viruses).
Some cationic and neutral lipids (liposomes) com-
plex with DNA to form structures that can transfect
DNA into cultured cells. The transfection is generally
not as efficient as that associated with viruses, and
expression is generally only transient. Nevertheless,
it is attractive because it avoids any theoretical con-
cerns of using viruses. Vaccines are currently under-
going trial using prostate-specific antigen and 17-1A
(a colorectal associated antigen) in liposome vectors
(189). DNA/polylysine complexes appear to be taken
up by some cells by receptor-mediated endocytosis.
Possible useful receptors include the transferrin re-
ceptor (317)and the polymeric IgA receptor (89).Ad-dition of an adenovirus helps to disrupt the endo-
some to release the vectored DNA (49). Naked DNA
is taken up by cells in some tissues (327).The uptake
is not very efficient but the effect can be long lasting.
It may be of use in vaccine applications, as both a
humoral and cellular immunity may develop. Naked
DNA has also been used in balloon angioplasty to
get transient expression of endothelial cell growth
factor (255).
Linkage of genes to form chimeric receptors has
also been proposed. Linkage of the signal transduc-
tion domain of IL-2 with the extracellular domain
of a growth-stimulating factor such as granulocyte-
macrophage colony-stimulating factor may provide
a means of promoting in vivo expansion of T cells
that are sensitized to specific viruses such as cyto-
megalovirus (254). A similar approach has been
taken with the herpes thymidine kinase and hygro-mycin genes (1781, and in an ex uiuo use of the same
technique, allografted T cells contained the same
combination to allow ganciclovir to be used to con-
trol graft-versus-host disease (192).
Cancer therapy trials are the most prominent area
of gene therapy research (189). It has been noticed
that tumor cells do not express or have low ex-
pression of major histocompatibility complex class I
or B7 antigens, resulting in poor or no antigen pres-
entation and thus preventing T-cell activation. Tu-
mor cells have been infected with viruses containing
the cDNA for these antigens and IL-2, and when re-
turned to the body can lead to systemic T-cell re-
sponses. This effect has been successful in animals
and is currently being used in human trials for the
treatment of melanoma, lung cancer, a range of solid
tumors (209) and renal cell carcinoma (271).
An alternative approach is the use of viruses with
recombinant tumor antigen genes. This has been
successful in forming tumor rejection immunity in
mice, but because most human tumor-associated
antigens are variations of normally expressed anti-
gens, they are likely to be only weakly immunogenic,
although this may be overcome by the addition of
further antigens to enrich the response. An alterna-
tive is to give the tumor additional anti-genes so they
can be recognized by cytolytic T cells. To this end,
the gene for HLA-B7 has been transfected into mela-
noma cells resulting in the tumors expressing HLA-
B7 (211)with subsequent regression of some lesions.
As mentioned above, another approach has been
the incorporation of the herpes thymidine kinase
gene into tumor cells, usually by direct injection of
viral particles into the tumor. The herpes thymidine
kinase then sensitizes the cells to ganciclovir, whichcan then be used to treat the tumor. There appears
to be an intracellular transfer of the phosphorylated
ganciclovir, which leads to many more tumor cells
being sensitized, this phenomenon being known as
the bystander effect (93). A similar approach has
been tried with cytidine deaminase and 5-fluorocy-
tosine (122). 'Ikials are currently under way using
gene sensitization for the treatment of glioblastom-
as, melanoma, mesothelioma and ovarian cancer.
A further application of gene therapy in cancer
treatment has been the concept of chemoprotec-
tion. Use of chemotherapy in the treatment of can-
131
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Gemmell et al
cer is often limited by the toxicity of the drugs on
normal cells. Bone marrow cells can be transfected
with MDR-1 (multi-drug resistance) gene ex vivo
such that when reintroduced, the patient can re-
ceive greater doses of chemotherapy without
threatening the marrow (125). The retrovirally in-duced cDNA is incorporated into relatively few
hematopoietic cells but each successive generation
will further propagate the resistance, allowing in-
creasing chemotherapy dosages (160). In a similar
vein, radiotherapy and chemotherapy sensitivity of
tumors has been attributed to the presence of
both damaged DNA and a functional p53 tumor
suppressor protein. The introduction of wild-type
p53 gene into resistant tumors has shown promis-
ing results by introducing sensitivity in animal
models (3241, and preliminary results in the treat-
ment of lung, liver and colorectal cancer have
been very encouraging 22, 168).
It may also be possible to treat cancer with genet-
ically modified tumor vaccines. Animal studies have
shown that ex uivo manipulation of tumor cells can
generate an immune response that is effective
against the original tumor when returned to the sub-
ject, but whether this will be effective in humans re-
mains to be seen (110). Difficulties in extrapolating
the technique to humans include obtaining suf-
ficient tumor tissue for vaccine preparation and the
use of a suitable vector for modifying the tumor cells
to make them more immunogenic.
Cytokine gene therapy
The use of genes encoding for cytokines or their an-
tagonists for the treatment of a number of disease is
also being tested. Viruses encoding the IL-lra have
been used effectively in animal models of arthritis
and also to prevent the re-occlusion of vessels fol-
lowing balloon angioplasty for atherosclerotic
plaques.
Cytokines can be used in a number of ways toachieve anti-tumor immunity. As mentioned above,
genes encoding for tumor-specific antigens and
cytokmes can be used in viral vectors or just the
cytokine gene itself can be transfected into the tu-
mor cell ex uivo or in vim The cross-regulation of
Thl and Th2 responses by IFN-y, IL-4 and 1L-10
have led to the study of cytokines for use in shift-
ing the balance towards a cell-mediated Thl re-
sponse. IL-10 is known to downregulate the ex-
pression of B7 and major histocompatibility com-
plex antigens (64), which have low expression on
tumor cells. Transfection of tumor cells with vari-
ous cytokines (tumor necrosis factor, IL-2, IFN-y,
IL-4 and granulocyte-macrophage colony-stimulat-
ing factor) have all been shown to lead to tumor
rejection in mice, and in some cases elimination
or reduced growth of the tumor (169). There is
currently no consensus as to which cytokine andwhich vector is the most useful clinically in terms
of actual useful treatment as opposed to just look-
ing at the immune response (43).
Despite some very promising results, it should be
remembered that gene therapy is still very much in
its infancy, and while many applications seem poss-
ible there are often many pitfalls in achieving a clin-
ically significant result. Such difficulties are high-
lighted by the trials to achieve factor VIII expression
in retrovirally transfected fibroblasts, muscle cells
and endothelial cells (126).
Conclusion
Understanding of the pathogenesis of periodontal
disease has made enormous progress over the past
5 years, but this progress has recognized higher level
complexities hitherto unknown. The concept of Th l
and Th2 cells based on their cytokine profiles led to
the development of hypotheses for the pathogenesis
of periodontal disease that highlight the concept of
susceptibility and nonsusceptibility for the first time.
These hypotheses have provided a framework for the
study of cytokines in periodontal disease that has
produced somewhat conflicting results. Variation in
results reported by different laboratories, however,
cannot always be explained by the techniques used,
and patient selection probably has a major role. The
conflicting results in many of these studies make it
clear that accurate criteria for assessment of disease
activity and for patient susceptibjlity are required to
allow meaningful interpretation of data. Prediction
of clinical disease activity in patients is not yet poss-ible, and only the measurement of past activity is
currently available. The establishment of a means for
classifylng patients as susceptible or nonsusceptible
and sites as stable or progressive is therefore necess-
ary to define patient selection more precisely. If this
is achieved, it may then be possible to test the Thl/
Th2 hypothesis (74, 282) and to determine the role
of IL-10, other cytokines, cytokine inhibitors and
prostaglandins, in controlling disease progression.
Only then will it be possible to design specific cyto-
kine or gene therapies for the treatment of peri-
odontal disease.
132
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References
1.Allison JP. CD27-B7 interactions in T-cell activation. curr
Opin Imrnunol 1994: 6 414-419.
2. Angelini SM, TrevinoAC, Novak MJ. Mechanisms of neu-
trophil immobilization by membrane vesicles of Porphyr-ornonus gingivufis. Dent Res 1994: 73: 347 (abstr 1961).
3. Anderson W Human gene therapy. Science 1992: 256:
808-813.
4. Aoyagi T, Sugawara-Aoyagi M, Yamazaki K Ham K In-
terleukin 4 (IL-4) and IL-6-producing memory T-cells in
peripheral blood and gingival tissues in periodontitis pa-
tients with high serum antibody titers to Porphyrornonas
gingivulk Oral Microbiol Immunol 1995 1 0 304-310.
5. Arai H, Nomura Y Kinoshita M, Shimizu H, Ono K, Goto
H, Takigawa M, Nishimura F, Washio N, Kurihara H, Mu-
rayama Y. Response of human gingival fibroblasts to
prostaglandins.1Periodont Res 1995 3 0 303-311.
6. ArendW nterleukin 1 receptor antagonist.A new mem-
ber of the interleukin 1 family. J Clin Invest 1991: 88:1445-1451.
7. Asnis L, GaspariA. Cutaneous reactions to recombinant
cytokine therapy. J Am Acad Dermatoll995: 33 393-410.
8. Attstrom R, Egelberg J. Emigration of blood neutrophils
and monocytes into the gingival crevice. J Periodont Res
1970:5: 48-55.
9. Attstrom R. Studies on neutrophil polymorphonuclear
leukocytes at the dento-gingival junction in gingival
health and disease. J Periodont Res 1971: 8(suppl): 1-15.
10. Audibert FM, Lise LD. Adjuvants: current status, clinical
perspectives and future prospects. Immunol Today 1993:
11. Balkwill FR, Burke E The cytokine network. Immunol To-
day 1989: 9: 299-304.12. Bancroft GJ. The role of natural killer cells in innate resist-
ance to infection. Cum Opin Immunol 1993:5: 503-510.
13. Barnes PI, Adcock I. Anti-inflammatory actions of ster-
oids: molecular mechanisms. Trends Pharmacol Sci 1993:
14: 436-441.
14. Barnett J, Chow J, Ives D, Chiou M, Mackenzie R, Osen E,
Nguyen B, Tsing S, Bach C, Freire J, Chan H, Sigal E,Ra-
mesha C. Purification, characterization and selective inhi-
bition of human prostaglandin GIH synthase 1 and 2 ex-
pressed in the baculovirus system. Biochim Biophys Acta
1994: 1209: 130-139.
15. Bertolini DR, Nedwin GE, Bringman JS, Smith DD, Mundy
GR. Stimulation of bone resorption and inhibition of for-
mation in vitro by human tumor necrosis factors. Nature1986: 319: 516-518.
16. Bevilacqua MI: Pober JS, Wheeler ME, Cotran RS, Gim-
brone MA Jr. Interleukin 1 acts on cultured human vascu-
lar endothelium to increase the adhesion of polymorpho-
nuclear leukocytes, monocytes, and related leukocyte cell
lines. J Clin Invest 1985: 76: 2003-2011.
17. Bigler CF, Noms DA, Weston WL, Arend WP. nterleukin-1
receptor antagonist production by human keratinocytes. J
Invest Derrnatol 1992: 9 8 3844.
18. Birkedal-Hansen H. Roles of cytokines and inflammatory
mediators in tissue destruction. J Periodont Res 1993 28
500-510.
19. Blau H, Springer M. Gene therapy a novel form of drug
delivery. N Engl J Med 1995: 333: 1204-1207.
14: 281-284.
20. Bloom BR, Salgame P, Diamond B. Revisiting and revising
suppressor T cells. Immunol Today 1992: 13: 131-136.
21. Bohjanen PR, Okajima M, Hodes RJ. Differential regula-
tion of interleukin4 and interleukin 5 gene expression: a
comparison of T-cell gene induction by anti-CD3 anti-
body or by exogenous Iymphokines. Proc Natl Acad Sci U
S A 1990 87: 5283-5287.22. Bookstein R, Demers W, regory R, Manevol D, Park J
Wills K. p53 gene therapy in vim of hepatocellular and
liver metastatic colorectal cancer. Semin Oncol 1996:23:
23. Boyce S, Chan CC, Gordon R, Li CS, RodgerW Webb JK,
Rupniak NM, Hill RG. L-745,337: a selective inhibitor of
cyclooxygenase-2 elicits antinociception but not gastric
ulceration in rats. Neuropharmacol 1994:33: 1609-161 1.
24. Brach MA, DeVos S, Gruss HJ, Herrmann E Prolongation
of survival of human polymorphonuclear neutrophils by
granulocyte-macrophage colony-stimulating factor is
caused by inhibition of programmed cell death. Blood
1992 80: 2920-2924.
25. Brown M, Hu-Li J Paul WE. IL-4IB cell stimulatory factor1 stimulates T cell growth by an IL-2-independent mech-
anism. J Immunol 1988: '131: 504-511.
26. Caillon P Saffar J. Improvement of gingival and alveolar
bone status in periodontitis-affected hamsters treated
with 15-methyl prostaglandin El , J Periodont Res 1994:
29: 13845.
27. CarpenterAB, Sully EC, Ranney RR, Bick PH. T-cell regula-
tion of polyclonal B-cell activation induced by extracts of
oral bacteria associated with periodontal diseases. Infect
Immun 1984: 43: 326-336.
28. Carter LL, Dutton RW 'Qpe 1 and 'Qpe 2: a fundamental
dichotomy for all T-cell subsets. Curr Opin Immunoll996:
8: 336-342.
29. CassatellaMA, GasperiniS, Calzetti F, McDonald PI: a i n -chieri G. Lipopolysaccharide-inducednterleukin-8 gene
expression in human granulocytes: transcriptional inhi-
bition by interferon-gamma. Biochem J 1995: 310: 751-
755.
30. Cassatella MA, Meda L, Bonora S, Ceska M, Constantin G.
Interleukin 10 (IL-10) inhibits the release of proinflam-
matory cytokines from polymorphonuclear leukocytes.
Evidence for an autocrine role of tumor necrosis factor
and IL-1 beta in mediating the production of IL-8 trig-
gered by lipopolysaccharide. J Ekp Med 1993: 178: 2207-
2211.
31. Cassatella MA, Meda L, GasperiniS, Calzetti F, Bonora S.
Interleukin 10 (IL-10) upregulates IL-1 receptor antagon-
ist production from lipopolysaccharide-stimulated hu-man polymorphonuclear leukocytes by delaying mRNA
degradation. J Exp Med 1994: 179: 1695-1699.
32. Centrella M, McCarthy TL, Canalis E. Skeletal tissue and
transforminggrowth factor p. FASEB J 1988: 2: 3066-3073.
33. Chan C, Boyce S, Brideau C, Ford Hutchinson AW Gordon
R, Guay D, Hill RG, Li CS, Mancini J, Penneton M, Prasit
P, Rasori R, Riendeau D, Roy D, Tagari I: Vickers P, Wong
E, Rodger I. Pharmacology of a selective cyclooxygenase-
2 inhibitor, L-745,337: a novel nonsteroidal anti-inflam-
matory agent with an ulcerogenic sparing effect in rat and
nonhuman primate stomach. J PharmacolExp Ther 1995:
34. Chan SH, Perussia B, Gupta yWKobayashi M, Pospisil M,
Young HA, Wolf SE Young D, Clark SC, Trinchieri G. In-
101-107.
274 1531-1537.
133
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 23/32
Gemmell et al.
duction of interferon gamma production by natural killer
cell stimulatory factor: characterization of the responder
cells and synergy with other inducers. J Exp Med 1991:
173: 869-879.
35. Chanmugam P, Feng L, Liou S, Jang BC, Boudreau M, Yu
G, Lee JH, Kwon HI, Beppu T, Yoshida M, Xia Y,Wilson C,
Hwang D. Radicicol, a protein tyrosine kinase inhibitor,suppresses the expression of mitogen-inducible cyclooxy-
genase in macrophages stimulated with lipopolysacchar-
ide and in experimental glomerulonephntis. J Biol Chern
1995: 270: 5418-5426.
36. Chen PB, Davern LB, chifferle R, Zambon IJ . Protective
immunization against experimental Bacteroides (Porphyr-
omonus) gingiualis infection. Infect Immun 1990: 58:
3394-3400.
37. Clagett ]A, Page RC. Insoluble im mun e complexes and
chronic periodontal diseases in man and the dog. Arch
Oral Biol 1978: 23: 153-165.
38. Clemens MJ. In: Read Ap: Brown T, ed. Cytokines. Oxford:
Bios Scientific Publishers, 1991.
39. Coffman RL, Carty I. A T cell activity that enhances poly-clonal IgE production and its inhibition by interferon-
gamma. J Immunol 1986: 136: 949-954.
40. Coffman RL,Ohara J Bond Mw arty 1 Zlotnik A, Paul
WE. B cell stimulatory factor-I enhances the IgE response
of lipopolysaccharide-activated cells. J Immunol 1986:
136: 4538-4541.
41. Cole KC, Seymour GJ, Powell RN. The autologous mixed
lymphocyte reactions (AMLR) using periodontal lympho-
cytes. 1 Dent Res 1986: 65: 473, abstract no. 16.
42. Cole KC, Seymour GJ, Powell RN. Phenotypic and func-
tional analysis of T cells extracted f rom chronically in-
flamed human periodontal tissues. J Periodontol1987: 58:
43. Colombo M, Rodolfo M. Tumor cells engineered to pro-duce cytokines or cofactors as cellular vaccines: do ani-
mal studies really support clinical trials. Cancer Immunol
Immunother 1995: 41: 265-270.
44. Colotta F Re E Polentarutti N, Sozzani S, Mantovani A.
Modulation of granulocyte survival and programmed cell
death by cytokines and bacterial products. Blood 1992:
80: 012-2020.
45. Cominelli E Nast CC, Clark BD, Schindler R Lierena R
Eysselein VE, hompson RC, Dinarello CA. Interleukin 1
(IL-1) gene expression, synthesis, and effect of specific IL-
1 receptor blockade in rabbit immune complex colitis. J
Clin Invest 1990: 86: 972-980.
46. Cope AE Aderka D, Doherty M, Engelmann H, Gibbons
D, Jones AC, Brennan FM, Maini RN, Wallach D, Feld-mann M. Increased levels of soluble tumor necrosis
factors in the sera and synovial fluid of patients with
rheumatic diseases. Arthritis Rheum 1 992 35: 1160-
1169.
47. Cosman D, Lyman SD, Idzerda RL. Beckmann MI? Park
LS,Goodwin RG, March CJ. A new cytokine receptor su-
perfamily. Trends Biochern Sci 1990: 15: 265-270.
48. Crystal R, McElvaney N, Rosenfeld M, hu C-S, Mastrang-
eli A, Hay JG, Brody SL, Jaffe HA, Eissa NT, Dane1 C. Ad-
ministration of an adenovirus containing the human
CFTR cDNA to the respiratory tract of individuals with
cystic fibrosis. Nature Genet 1994: 8: 42-47.
49. Curie1 D, Wagner E, Cotten M, Birnstiel M, garwal S. ti
CM, Loechel S H u PC. High efficiency gene transfer med-
569-573.
iated by adenovirus coupled to DNA-polylysine complex-
es. Hum Gene Ther 1992: 3: 147-154.
50. Dayer JM, Beutler B, Cerami A. Cachectinltumor necrosis
factor stimulates collagenase and prostaglandin E2 pro-
duction by hum an synovial cells and dermal fibroblasts. J
Exp Med 1985: 162: 2163-2168.
51. De Maeyer E, De Maeyer-Guignard J. Interferon-y. CurrOpin Immunol 1992 4 321-326.
52. Del Prete G, De Carli M , Almerigogna E Giudizi MG, Bi-
agiotti R, Romagnani S.Human IL-10 is produced by both
m e helper (Thl ) and lLpe 2 helper (Th2) T cell clones
and inhibits their antigen-specific proliferation and cyto-
kine production. J Immunoll993: 150: 353-360.
53. Del F'rete G, Maggi E, Parronchi P, Chretien I, TiriA, Mac-
chia D, Ricci M, Banchereau J, De Vries J Romagnani S.
IL-4 is an essential factor for the IgE synthesis induced in
virro by human T cell clones and their supernatants. J
Immunol 1988: 140: 4193-1198.
54. De Waal Malefyt R, Yssel H, de Mies JE. Direct effects of
IL- 10on subsets of hu man CD4+T cell clones and resting
T cells. Specific inhibition of IL-2 production and prolifer-ation. Immunol 1993: 150: 4754-4765.
55. De Wad Malefyt R Figdor C, Huijbens R, Mohan-Peterson
S, Bennett B, Culpepper J Dang W, Zurawski G, de Vries
JE. Effects of IL-13 on phenotype, cytokine production,
and cytotoxic function of human monocytes. J Immunol
1993: 151: 6370-6381.
56. De Wad Malefyt R, Yssel H, Roncarolo M-G, Spits H, de
Vries IE. Interleukin-10. Curr Opin Immunol 1992: 4: 314-
320.
57. Dewhirst F, Moss D, Offenbacher S, Goodson JM. Levels
of prostaglandin Ez. hromboxane, and prostacyclin in
periodontal tissues. J Periodont Res 1983: 18: 156-163.
58. Dietrich J Goodson JM, Raisz LG. Stimulation of bone
resorption by various prostaglandins in organ culture.Prostaglandins 1975: 10: 231-240.
59. Dinarello CA. Interleukin-1. Rev Infect Dis 1984: 6 51-95.
60. Dinarello CA. The biology of interleukin 1 and compari-
son to tumor necrosis factor. Immunol Lett 1987: 16 227-
232.
61. Dinarello CA. The role of interleukin-1 in host responses
to infectious diseases. Infect Agents Dis 1992: 1: 227-236.
62. Dinarello CA, Wolff SM. The role of interleukin-1 in dis-
ease. N Engl J Med 1993: 328: 106113.
63. Ding L, Shevach EM. IL-10 inhibits mitogen-induced T
cell proliferation by selectively inhibiting macrophage co-
stirnulatory function. J Immunol 1992: 148: 3133-3139.
64. Ding L, Linsley PS, Huang L-Y, Germain RN, hevach EM.
IL- 10 inhibits macrophage costimulatory activity byselectively inhibiting th e up-regula tion of B7 expression.
J Imrnunol 1993: 151: 1224-1234.
65. Distel M, Mueller C, Bluhmki E, Fries J. Safety ofmelox-
icam: a global analysis of clinical trials. Br J Rheumatol
66. Donahue RE,Wang EA, Stone DK, Kamen R, Wong GG,
Sehgal PK, Nathan DG, Clark SC. Stimulation of haema-
topoiesis in primates by continuous infusion of recorn-
binant human GM-CSE Nature 1986: 321: 872-875.
67. Dongari-Bagtzoglou A, Ebersole J. Production of inflam-
matory mediators and cytokines by human gingival
fibroblasts following bacterial challenge. J Periodont Res
1996: 31: 90-98.
68. Donnelly RE Fenton MI, Finbloom DS, Gerrard TL. Differ-
1996: 35(SUppl 1): 68-77.
134
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 24/32
Cytokines and prostaglandins in periodontal disease
ential regulation of IL-1 production in hum an monocytes
by IFN-y an d IL-4. J Imm uno l 199 0 145: 569-575.
69. Drevlow B, h v i s R, Haag M, Sinacore J, Jacobs C, Blosch
C, Beck C, Landay A, Moreland L, Pope R. Phase I study
of recombinant human interleukin- 1 receptor (RHUIL-
1R) administered su bcuta neou sly in patients with active
rheumatoid arthritis. Arthritis Rheum 1994: 37: S339(abstr 1070).
70. Dubois CM, Ruscetti Fw Palaszynski EW, Falk LA, Op-
penheim JJ, Keller JR. Transforming growth factor fi is a
potent inhibitor of interleukin 1 (IL-1) receptor ex-
pression: proposed mec hanism of inhibition of IL-1 ac-
tion. J Exp Med 1990: 172: 737-744.
71. DuB ois R, Awad J, Mo rrow J Roberts L, Bishop I? Regula-
tion of eicosanoid production and mitogenesis in rat in-
testinal epithelial cells by transforming growth factor-a
an d phorb ol ester. J Clin Invest 1994: 93: 493-498.
72. Eastcott W ,Yamashita K, Taubman MA, Harada Y Smith
DJ. Adoptive transfer of cloned T helpe r cells ameliorates
periodontal disease in n ude rats. Oral Microbiol Immun ol
1994:9: 284-289.73. Ebe rsole J Singer R, Steffen sen B, Filloon T, Kornm an KS.
Inflammatory mediators and immunogloblulins in GCF
from healthy, gingivitis and periodontitis sites. J Peri-
odont Res 1993: 28: 543-546.
74. Ebersole JL, Taubman MA. The protective nature of host
responses in periodontal diseases. Periodonto12000 1994:
75. El Attar TM. Prostaglandin E, in hu ma n gingiva in health
and disease and its stimulation by female sex steroids.
Prostaglandins 1976 11: 331-341.
76. El Attar T, Lin H. Prostaglandins in gingiva of patients
with periodontal disease. J Periodontol 1981: 5 2 16-19.
77. El Attar T, Lin H. Relative conversion of arachidonic acid
through lipoxygenase and cyclooxygenase pathways by
homogenates of diseased periodontal tissues. J Oral
Pathol 1983: 1 2 7-10.
78. El Attar T, Lin H, Tira D. Arachidonic acid metabolism in
inflamed gingiva an d its inhibition by anti-inflammatory
drugs. J Periodontol 1984: 55: 536-539.
79. El Attar T, Lm H. Prostaglandin E2 antagonizes gingival
fibroblast proliferation stimulated by interleukin-lp.
Prostaglandins Leukotr Essen Fatty Acids 1993: 4 9 847-
850.
80. Elliott M, Maini R. Anti-cytokine therapy in rheumatoid
arthritis. BailliBre’s Clin Rhe uma tol 1995: 9: 63 36 52 .
81. Elliot M, Maini R, Feldm an M , Kalden JR, Antoni C, Smol-en JS, eeb B, Breedveld FC, Macfarlane JD , Bijl H. Ran-
domised double-blind comparison of chimeric mono-
clonal antibody to tumor necrosis factor a cA2) ersusplacebo in rheum atoid arthritis. Lancet 1994: 344 (8930):
1105-1110.
82. Elliot M, Ma ini R, Feldm an M, Long-F ox A, Cha rles P, BijlH, Woody JN. Repeated therapy with monoclonal anti-
body to tumor necrosis factor a ( ) in patients with
rheum atoid arthritis. Lancet 1994:344 1125-1 128.83. Ellis SD, Tucci MA, Serio FG, Johnson RB. IL-12 in peri-
odon tal disease. J Dent Res 1996: 75: 322 (ab str 2440).
84. Engelhardt G, Bogel R, Schnitzler C, Utzmann R. Melox-
icam: influence on arachidonic acid metabolism. 11. In
uivo findings. Biochem Pharmacol 1996: 51: 29-38.85. Enk AH, Angeloni VL, Udey MC, Katz SI. Inhibition of
Langerhans cell antigen-presenting function by IL-10. J
Immunol 1993: 150: 4754-4765.
5: 112-141.
86. Essner R, Rhoades K, McBride WH, Morton DL, Econom-
ou JS. IL-4 dow n-regulates IL-1 and TNF gene expression
in human monocytes. J Im mu nol 1989: 142: 3857-3861.
87. Evans RT, Klausen B, Sojar HT, Bedi GS, Sfintescu C, Ram-
amurthy NS, Golub LM, Genco RJ. Immunization with
Porphyromonas (Bacteroides)gingivalis fimbriae protects
against periodontal destruction. Infect Immun 1992: 60:2926-2935.
88. Fabry Z, Sandor M, Gajewski TE Herlein JA, Waldschmidt
MM, Lynch RG, Hart MN. Differential activation of Thl
and Th2 CD4+ cells by murine brain microvessel endo-
thelial cells and smooth musclelpericytes. J Immunol
1993: 151: 3 8 4 7 .
89. Ferkol T,Kaetzel C, Davis F Gene transfer into respiratory
epithelial cells by targeting the polymeric immunoglob-
ulin receptor. J Clin Invest 1993: 92: 2394-2400.
90. Finkelman FD, Katona IM, Mosmann TR, Coffman RL.
IFN-1 regulates th e isotypes of Ig secreted d uring in vivo
humoral im mun e responses. J Immunol 1988: 140: 1022-1027.
91. Fior entino DF, Zlotn ik A, Vieira P, Mosmann TR, HowardM, Moore W, O’Garra A. IL-10 acts on the antigen-pre-
senting cell to inhibit cytokine production by Th l cells. J
Immunol 1991: 146: 3444-3451.
92. Frankenburg S, Kofsky Y Gross A. In vitro secretion of
cytokines by human mononuclear cells of individuals
durin g and after cutan eous leishmaniasis infection. Para-
site Immunol 1993: 15: 509-512.93. Freeman S, Abboud C, Whartenby KA, Packman CH, Koe-
plin DS, Moolten FL, Abraham GN. The “bystander ef-
fect.” Tumor regression when a fraction of the tumor
mass is genetically modified. Cancer Res 1993: 53: 5274-
5283.
94. Fu N asferrer JL, Seibert S, R a z A, Needleman I? The
induction and suppression of prostaglandin H2 synthase
(cyclooxygenase) n hu m an monocytes. Biol Chem 1990:
95. Fujihashi K Kono Y, Yamamoto M, McGhee JR, Beagley K
Aicher WK, Kiyono H. Interleukin p rodu ction by gingival
mononuclear cells isolated from adult periodontitis pa-
tients. J Dent Res 1991: 70: 50 (abstr 2269).
96. Fujihashi K, Yamamoto M, McGhee JR, Kiyono H. Q-pe
1I-e 2 cytokine pro du ctio n by CD4+ T cells in adult
periodontitis. J De nt Res 1994: 73: 204 (abstr 818).
97. Gaffer A, Scherl D, Afflitto J, Coleman E. The effect of
triclosan on mediators of gingival inflammation. J Clin
Periodontol 1995: 22: 480-484.
98. Gajewsk i TF, Pin nas M, Wong T, Fitch W .Murine Thl and
Th2 clones proliferate optimally in response to distinct
antigen-presenting cell populations 1 Immunol 1991: 146:1750-1758.
99. Garrison S, Holt S, Nichols E Lipopolysaccharide-stimu-
lated PGE2 release from hu m an m onocytes. J Periodontol1988: 59: 684-687.
100. Ge T, Hugh es H, Ju nq ue ro DC, Wu KK, Vanhoutte PM, Boul-
anger CM. En dothelium-depen dent contractions are as-
sociated with both augm ented expression of prostaglandin
H synthase-1 an d hypersensitivity to prostaglandin H2 inth e SHR aorta. Circ Res 1995 : 76: 1003-1010.
101. Gemmell E, Feldner B, Seym our GJ. CD45RO an d CD45RApositive cells in peripheral blood a nd periodontal lesions
before and after stimulation with Porphyrornonas g ing i -
valis a n d Fusobacteriurn nucleaturn. Oral Microbiol Im-
mu no l 1992: 7: 84-88.
265: 16737-16740.
135
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 25/32
Gemmell et al.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
Gemmell E, Kjeldsen M, Yamazaki K, Nakajima T, Aldred
MJ, Seymour GJ. Cytokine profiles of Porphyromonas gin-
givalisreactive T lymphocyte lines and clones derivedfrom I? gingivalis-infected subjects. Oral Dis 1995: 1: 139-
146.
Gemmell E, Seymour GJ. Interleukin 1, interleukin 6 a n d
transforming growth factor-@ roduction by hum an gingi-val monon uclear cells following stimu lation with Porphy
romonaS gingivalis a n d Fusobacterium nucleaturn J Peri-
odo nt Res 1992: 28: 122-129.
Gemmell E, Seymour GJ. Modulation of immune re-
sponses to periodontal bacteria. Cum Opin Periodontol
Genco RJ, Mashimo PA, Krygier G, Ellison SA. Antibody-
mediated effects on the periodontium. J Periodontol
1974: 45: 330-337.
Genco RJ, Zam bon JJ, Christersson LA. The origin of peri-
odontal infections. Adv Dent Res 1988: 2: 245-259.
Geng Y, Blanco F, Cornelisson M, Lotz M. Regulation of
cyclooxygenase-2 expression in normal human articular
chondrocytes. J Immunol 1995: 155: 79 64 01 .Ghezzi P, Dinarello CA. L-1 induces IL - 1 . 3. Specific inhi-
bition of IL-1 production by IFN-y. J Immunol 1988: 140:
42364244.
Gierse JK$Haus er SD, Creely DP, Koboldt C,Rangwala SH,
Isajson PC, Siebert K. Expression a nd selective inhibition
of the constitutive and inducible forms of human cyclo-
oxygenase. Biochem J 1995: 305(part 2): 479-484.
Gilboa E. Immunotherapy of cancer with genetically
modified tum or vaccines. Semin Oncol 1996: 23: 101-107.
Goldhaber F Tissue culture studies of bone as a model
system for periodontal research. J Dent Res 1971: 50: 278-
285.
Goldhaber P, Rabadjija L, Beyer WR, Kornhauser A. Bone
resorption in tissue culture and its relevance to peri-odon tal disease. J Am Den t Assoc 1973: 87: 1027-1033.
Golumbeck PT, azenby AJ, Levitsky HI, Jaffee LM, Karas-
uyama H, Baker M, Pardoll DM. Treatment of established
renal cancer by tumour cells engineered to secrete in-
terleukin-4. Science 1991: 254: 713-716.
Gomes BD, Hausmann E, Wienfeld N, De Luca C. Prosta-
glandins: bon e resorption stimu lating factors released
from mon key g ingiva. Calcif Tissue Res 1976 19: 285-293.
1994: 28-38.
115. Goodson JM, Derwhirst E Brunetti A. Prostaglandin E2
levels and human periodontal disease. Prostaglandins
1974: 6: 81-85.
116. Graham BS, Henderson GS, Tang Y-W, Lu X, Neuzil KM,
Colley DG. Priming immunization determines T helper
cytokine mRNA expression pa tterns i n lungs of m ice chal-lenged with respiratory syncytial virus. J Immunol 1993:
117. Granowitz EV Clark BD. Effect of interleukin-1 ( I L - 1 )
blockade o n cytokine synthesis: IL- 1 receptor a ntagonist
inhibits IL-1 induced cytokine synthesis and blocks the
binding of IL-1 o its type 11 receptor on human mono-
cytes. Blood 1992: 79: 2356-2363.
118. Grimm E, Mazumder A, Zha ng H, Rosenberg S.Lympho-
kine-activated killer cell phenomenon. Lysis of natural
killer-resistant fresh solid tum or cells by interleukin 2-
activated autologous human peripheral blood lympho-
cytes. J Exp Med 1982: 155: 1823-1841.
119. Griswold DE, Hillegass LM, Breton JI, Esser KM, Adams
JL. Differentiation in vivo of classical non -steroid al antiin-
151: 2032-2040.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129
130.
131.
132.
133.
134.
flam mato ry drug s from cytokine-suppressive a ntiin-
flammatory drugs and other pharmacological classes
using mouse tumour necrosis factor alpha production.
Drugs Exp Clin Res 1993: 19: 243-248.
Griswold DE, M arshall P J, Lee JC, Webb EF, Hillegass LM,
Wartell 1, Newton J Jr, Han na N. Pharm acology of the pyr-
roloimidazole, SK&F 105809.11. Antiinflammatory activityand inhibition of mediator production in vivo. Biochem
Pharmacol 1991:4 2 825-831.
Grossman M, Raper S , Kozarsky K, Ste in E, Eng elhardt J
Muller D, Lupien PJ, Wilson JM. Successful ex vim gene
therapy directed to liver in a patient with familial hyper-
cholesterolaemia. Nature Genet 1994 6: 335-341.
Grove KL, Guo X Liu SH, Gao Z, Ch u CK, Ch eng YC. An-
ticancer activity of beta-L-dioxolane-cytidine, novel
nucleoside analogue with the u nnatural L configuration.
Cancer Res 1995: 55: 3008-3011.
Hamblin AS. In: Male D, ed. Cytokines and cytokine re-
ceptors. Oxford: Oxford University Press, 1993.
Ha mm erb erg C, Arend W, Fisher G, Chan L, Berger A,
Haskill J, Voorhees J, Co oper K. Interleukin-1 receptor an-tagonist in normal and psoriatic epidermis. J Clin Invest
Hanania E, Fu S, Zu Z, Hegewisch Becker S , Korbling M,
Hester J, Durett A, Andreeff M, Mechetner E, Holzmayer
T, Roninson I, Giles E, Bere nson R, Heimfeld S,Deisscroth
A. Chem otherapy resistance to taxol in clonogenic pro-
genitor cells following transduction of CD34 selectedmarrow and peripheral blood cells with a retrovirus that
contai ns the MDR-1 chemo therap y resistance gene. Gene
Ther 1995: 2: 285-294.
Hanania E, Kavanagh J, Hortobagyi G, Giles R, Champlin
R, Deisseroth A. Recent advances in the application of
gene therapy to hu ma n disease. Am J Med 1995: 99: 537-
552.Harrell J Stein S. Prostaglandin E2 regulates gingival
mononuclear cell immunoglobulin production. J Peri-
odontol 1995: 66: 222-227.
Harvey W, Bennett A. Prostaglandins in bone resorption.
Boca Raton, F L CRC Press, 1988.
Heasman P, Benn DK, Kelly F: Seymour R, Aitken D. The
use of topical flurbiprofen as an adjunct to non-surgical
management of periodontal disease. J Clin Periodontol
1993: 20: 457-464.
Heasman F Collins J, Offenbacher S. Changes in crevic-
ular fluid levels of in terleuk in-lp, leukotriene B4, rosta-
glandin E2, thromboxane B2 and tumour necrosis factor
n experimental gingivitis in humans. J Periodont Res
Heasman P, Offenbacher S , Collins I, Edwards G, Seymour
R. Flurbiprofen in the prevention and treatment of experi-
men tal gingivitis. J Clin Periodontol 1993: 20: 732-728.
Heas man PA, Seymour R. The effect of a systemically-ad-
ministered non-stero idal anti-inflammatory drug
(flurbiprofen) on experimental gingivitis in humans. J
Clin Periodontol 1989: 16: 551-556.
Heasman P, Seymour R, Kelly P The effect of systemicdly-
administered flurbiprofen as an adjunct to toothbrushing
on resolution of experim ental gingivitis. J Clin Peri-
odontol 1994: 21: 166-170.
Hendley TM, Steed RB, Galbraith GMF Interleukin-lp
gene expression in human oral polymorphonuclear
leukocytes. J Periodontol 1995: 66: 761-765.
1992:90: 571-583.
1993: 28: 241-247.
136
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 26/32
Cytokines and prostaglandins in periodontal disease
135. Higuchi M, Aggarwal BB. Modulation of two forms of tu-
mor necrosis factor receptors and their cellular response
by soluble receptors and their monoclonal antibodies. J
Biol Chem 1992: 267: 20892-20899.
136. Honig J, Rordorf-Adam C, Siegmund C, Wiedemann W,
bard E Interleukin-1 beta (IL-lp) concentration in gingi-
va tissue from periodontitis patients and healthy controlsubjects. J Periodont Res 1989: 24: 362-367.
137. HoogerbruggeI:Vassen J, BeusechannV, Valerio D. Treat-
ment of patients with SCID due to ADA deficiency by
autologous transplantation of genetically-modified bone
marrow cells. Hum Gene Ther 1992 3 553-558.
138. Howard M, O'Garra A. Biological properties of Interleukin
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
10. Immunol Today 1992 13: 196-200.
Howell TH. Blocking periodontal disease progression with
anti-inflammatory agents. J Periodontol 1993: 6 4 828-
833.
Howells GL. Cytokine networks in destructive periodontal
disease. Oral Dis 1995:1: 266-270.
Hughes FJ, Howells GL. Interleukin-6 inhibits bone for-
mation in uitro. Bone Min 1993: 21: 21-28.Hyams IS, Fitzgerald JE, Wyzga N, Muller R, Treem WR,
JustinichCJ, Kreutzer DL. Relationship of interleukin-1re-
ceptor antagonist to mucosal inflammation in inflamma-
tory bowel disease. J Pediatr Gastroenterol Nutr 1995:21:
419-425.
Inoue T, Asano Y,Matsuoka S,Furutani-SeikiM, Aizawa
S, Nishimura H, Shirai T, Tada T. Distinction of mouse
CD8+ suppressor effector T cell clones from cytotoxic T
cell clones by cytokine production and CD45 isoforms. J
Isakson I: Siebert K, Masferrer J, Salvemini D, Lee L,
Needleman P. Discovery of a better aspirin. Adv Prosta-
glandin Thromboxane Ledcot Res 1995: 2 3 49-54.
Ishii T, Mahanonda R, Seymour GI. The establishment ofhuman T cell lines reactive with specific periodontal bac-
teria. Oral Microbiol Immunol 1992: 7: 225-229.
Ito H-0 , Shuto T, Takada H, Koga T, Aida Y,HirataM, Koga
T. Lipopolysaccharides from Potphyromonas gingiualis,
Prevotella intermedia and Actinobacillus actinomycetem-
comitans promote osteoclast differentiation in vim.Arch
Oral Biol 1996: 41: 439-444.
Jeannin I: DelnesteY,Life P. GauchatJE Kaiserlian D, Bon-
nefoy JY. Interleukin-12 increases interleukin-4 produc-
tion by established human Tho and Th2-lie T cell clones.
Eur J Immunol 1995: 25: 2247-2252.
Jinquan T, Grenhoj Larsen C, Gesser B, Matsushima K,
Thestrup-PedersenT.Human It-10 is a chemoattractant
for CD8+ T lymphocytes k d n inhibitor of IL-8-inducedCD4+ T lymphocyte migration. J Immunol 1993: 151:
4545-4551.
Jones D, Carlton D, McIntyre T, Zimmerman G, Prescott
S.Molecular cloning of human prostaglandin endoperoxi-
dase synthase type 11 and demonstration of expression in
response to cytokines. J Biol Chem 1993: 268: 9049-9054.
Karatzas S, Novak MJ, Blieden TM. Cytokine production
by Porphyromonas gingivalisspecific human T cells. J
Dent Res 1996 75: 322 (abstr 2435).
Kelso A. Cytokines in infectious disease. Aust Microbiol
Kelso A. Thl and Th2 subsets: paradigms lost? Immunol
Today 1995: 16: 374-379.
Kelso A, Troutt AB, Maraskovsky E, Gough NM, Morris L,
IIIUINUIOI1993: 150: 2121-2128.
1990: 11: 372-376.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
Pech MH, Thomson JA. Heterogeneity n lymphokine pro-
files of CD4+ and CDB+ T cells and clones activated in
vivo and in vitro. Immunol Rev 1991: 123: 85-114.
Kesavalu L, Ebersole JL, Machen RL, Holt SC. Porphyro-
monas gingivalis virulence in mice: induction of immun-
ity to bacterial components. Infect Immun 1992: 60:
1455-1464.Kimura S, Fugimoto N, Okada H. Impaired autologous
mixed-lymphocyte reaction of peripheral blood lympho-
cytes in adult periodontitis. Infect Immun 1992:59: 4418-
4424.
Klein DC, Raisz LG. Prostaglandins: stimulation of bone
resorption in tissue culture. Endocrinology 1970: 86:
1436-1440.
Klein T, Nusing RM, Pfeilschifter J Ullrich V.Selective in-
hibition of cyclooxygenase 2. Biochem Pharmacol 1994:
48: 1605-1610.
Knight D, m n h H, Le J, Siege1 S, Shealy D, McDonough
M, Scallon B, Moore MA, Vicek J, Daddona P Ghrayeb
J. Construction and initial characterization of a mouse-
human chimeric anti-TNF antibody. Mol Immunol 1993:
Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan
S, Loudon R, Sherman E Perussia B, Tiinchien G. Identi-
fication and purification of natural killer cell stimulatory
factor (NKSF) a cytokine with multiple biologic effects o n
human lymphocytes.J Exp Med 1989 70 : 827-845.
Koq ON, Allay JA, Lee K, Davis BM, Reese JS, Gerson SL.
Transfer of drug resistance genes into hematopoietic pro-
genitors to improve chemotherapy tolerance. Semin On-
col 1996: 23: 46-65.
Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL,
Haines GK, Burdick MD, Pope RM, StrieterRM. Enhanced
production of rnonocyte chemoattractant protein-1 in
rheumatoid arthritis. J Clin Invest 1992: 90: 772-779.KoideM, Suda S,SaitohS,OfujiY Suzuki T,Yoshie H, Takai
M, OnoY, TaniguchiY, Hara K. In vivoadministration of IL-
l p accelerates silk ligature-induced alveolar bone resorp-
tion in rats. J Oral Pathol Med 1995: 2 4 420-434.
Kujubu D, Fletcher B, Vamum B, Lim R, Henchman H.
TIS10, a phorbol ester tumor promoter-inducible mRNA
from Swiss 3T3 cells, encodes a novel prostaglandin syn -
thaselcyclooxygenase gene. J Biol Chem 1991: 266:
12866-12872.
Kupper TS, Ballard DW, Chua AO, McGuire JS, Flood PM,
Horowitz MC, Langdon R, Lightfoot L, Gubler U. Human
keratinocytes contain mRNA indistinguishable from
monocyte interleukin- a and fi mRN4 keratinocyte epi-
dermal cell-derived thymocytes activating factor is ident-ical to interleukin-1. J Exp Med 1986: 164: 2095-2100.
Kutsch CL, Norris DA, ArendW umor necrosis factor-
alpha induces interleukin-1 alpha and interleukin-1 re-
ceptor antagonist production by cultured human kera-
tinocytes.J Invest Dermatol 1993: 101: 79-85.
Lamont AG, Adorini L. IL-12: a key cytokine in immune
3 0 1443-1453.
.~regulation. Immunol Today 1996: 17: 214-217.
167. Laneuville 0, Breuer DK, Dewitt DL, Hla T Funk CD,
SmithWL. Differential inhibition of human prostaglandin
endoperoxidase H synthases-1 and -2 by nonsteroidal
anti-inflammatory drugs. J Pharmacol Exp Ther 1994:
168. Larkin M. Promising results reported for lung cancer gene
271: 927-934.
therapy. Lancet 1996: 34 8 671.
137
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 27/32
Gemmell et al.
169. Lattime E,Lee S , Eisenlohr L, MastrangeloM. In situ cyto-
kine gene transfection using vaccinia virus vectors. Semin
Oncol 1996: 23:88-100.
170.Le J Vilcek J. Biology of disease. lbmor necrosis factor
and interleukin 1. Cytokines with multiple overlapping
biological activities. Lab Invest 1987: 3: 234.
171. Lee JC, Young PR. Role of CSBIp381RK stress responsekinase in LPS and cytokine signaling mechanisms. J Leu-
koc Biol 1996: 59: 152-157.
172. Lee S, Soyoola E, Chanmugam P, Hart S, Sun W Zhong
H, Liou S, Simmons D, Hwang D. Selective expression of
mitogen-inducible cyclooxygenase in macrophages
stimulated with lipopolysaccharide. J Biol Chem 1992:
267: 25934-25938.
173.Lewis RA. Interactions of eicosanoids and cytokines in
immune regulation. Adv Prostaglandin Thromboxane
Leukot Res 1990:20:170-178.
174.Lloyd AR,Oppenheim JJ. Polys lament: The neglected role
of the polymorphonuclear neutrophil in the afferent limb
of the immune response. Immunol Today 1992: 13: 169-
172.175.Loning T, Albers H, Lisboa B, Burkhardt A, Caselitz I.
Prostaglandin E and local immune response in chronic
periodontal disease. Immunohistochernicaland radioim-
munological observations. J Periodont Res 1980: 15: 525-
35.
176. Lopatin DE, lackburn E. Avidity and titer of immuno-
globulin G subclasses to P o r p h y r o m o m gingivalis in
adult periodontitis patients. Oral Microbiol Immunol
177.Lundgren M, Persson U, Larsson P, Magnusson C, Smith
CIE, HammarstrOm L, SeverinsonE. Interleukin4 nduces
synthesisof IgE and IgG4 in human B cells. Eur J Immun-
178.Lupton S Printon L, Kalberg V, Overall R. Dominant posi-tive and negative selection using a hygromycin phospho-
transferase thymidine kinase fusion gene. Mol Cell Biol
1991: 11: 3374-3378.
179.MacFarlane GD,Herzberg MC, Wolff LF,Hardie NA. Re-
fractory periodontitis associated with abnormal polymor-
phonuclear leukocyte phagocytosis and cigarette smok-
ing, 1Periodontol 1992: 63: 908-913.
180.Mahanonda R Seymour GJ, Powell LW Good ME Halliday
W. Effect of initial treatment of chronic inflammatory
periodontal disease on the frequencyof peripheral blood
T-lymphocytes specific to periodontopathic bacteria. Oral
Microbiol Immunol 1991:6: 21-227.
181.Mangan DF, Mergenhagen SE, Wahl SM. Apoptosis in hu-
man monocytes: possible role in chronic inflammatorydiseases. J Periodontol 1993:64: 61-466.
182. Mangan DF,Robertson B, Wahl SM. IL-4 enhances pro-
grammed cell death (apoptosis) in stimulated human
monocytes.J Immunol 1992: 148: 1812-1816.
183.Manhart SS,Reinhardt RA, Payne JB, Seymour GI, Gem-
mell E, Dyer IK Petro TM. Gingival cell IL-2 and IL-4 in
early-onset periodontitis. J Periodontol 1994: 65: 807-
813.
184. March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price
V, Gillis S , Henney CS, Kronheim SR, Grabstein K Conlon
P, Hopp T, Cosman D. Cloning, sequence and expression
of two distinct human interleukin- complementary
DNAs. Nature 1985: 315: 641-647.
185. Marks Jr S Miller S . Local infusion of prostaglandin E l
1992: : 332-337.
01 1989: 19: 1311-1315.
stimulates mandibular bone formation in uiuo. J Oral
Pathol 1988:17: 00-505.
186. Marks S,Miller S . Local delivery of prostaglandin El in-
duces periodontal regeneration in adult dogs. J Periodont
Res 1994:29:103-108.
187. Martin D, Near SL. Protective effect of the interleukin-1
receptor antagonist (IL-Ira) on experimental allergic en-cephalomyelitis in rats. J Neuroimmunol 1995: 61: 41-
245.
188. Masada MP, Persson R, Kenney JS, Lee SW, Page RC, Mi-
son AC. Measurement of interleukin-la and -1p n gingi-
val crevicular fluid implication for the pathogenesis of
periodontal disease. J Periodont Res 1990: 25: 156-163.
189. Mastrangelo M , Berd D, Nathan E Lattime E. Gene ther-
apy for human cancer: an essay for clinicians. Sem Oncol
190. Matsuki Y, Yamamoto T, Hara K. Detection of inflamrna-
tory cytokine messenger-RNA (mRNA)-expressing cells in
human inflamed gingiva by combined in situ hybridiza-
tion and immunohistochemistry. Immunology 1992: 7 6
42-47.191. Matsuki Y, Yamamoto T,Hara K. Localizationof interleu-
kin-1 (IL-1) mRNA-expressing macrophages in human in-
flamed gingiva and IL-1 activity in gingival crevicular
fluid. J Periodont Res 1993: 28: 35-42.
192. Mavilio E Ferrari G, Rossini S , Nobili N, Bonini C, Casorati
G, Traversari C, Bordignon C. Peripheral blood lympho-
cytes as target cells of retroviral vector-mediated gene
transfer. Blood 1994: 83: 1988-1997.
193.McKenzie AN, Culpepper JA, de Wad Malefyt R, Briere F,
Punnonen J Aversa G , Sat0 A, Dang W, Cocks BG, Menon
S , de Vries JE, Banchereau J Zurawski G. Interleukin 13,a
T-cell-derived cytokine that regulates human monocyte
and B-cell function. Proc Natl Acad Sci U S A 1993: 90:
3735-3739.194. Meghji S, Henderson B, Wilson M. High-titer antisera
from patients with periodontal disease inhibit bacterial
capsule-induced bone breakdown. J Periodont Res 1993:
28: 115-121.
195. Meikle MC, Heath JK Reynolds J]. Advances in under-
standing cell interactions in tissue resorption. Relevance
to the pathogenesis of periodontal diseases and a new
hypothesis. J Oral Path01 1986 15:239-250.
196. Meikle MC, Atkinson SJ, Ward RV, Murphy G, Reynolds JJ.
Gingival fibroblasts degrade type 1 collagen films when
stimulated with tumor necrosis factor and interleukin 1.
Evidence that breakdown is mediated by metalloprotein-
ases. J Periodont Res 1989:24 07-213.
197. Mendieta C, Reeve C, Romero J. Biosynthesisof prosta-glandins in gingiva of patients with chronic periodontitis.
J Periodontol 1985: 5 6 4-47.
198.Mingari MC, Moretta A, Maggi E, Pantaleo G, Gerosa F,
RomagnaniS , Moretta L. Frequent coexpression of cytoly-
tic activity and lymphokine production among human T
lymphocytes. Production of B cell growth factor and in-
terleukin 2 by T8+ and T4' cytolytic clones. Eur J Immun-
01 1984: 14: 1066-1069.
199. Mitchell J Akarasereenont P, Thiemermann C, Flower R,
Vane J. Selectivity of nonsteroidal antiinflammatory drugs
as inhibitors of constitutive and inducible cyclooxygen-
ase. Proc Natl Acad SciU S A 1993:90: 1693-11697.
200. Miyamoto T, Ogino N , Yamamoto S , Hayaishi 0. Purifi-
cation of prostaglandin endoperoxide synthetase from
1996: 23: 4-21.
138
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 28/32
Cytokines and p rostaglandin s in periodontal disease
bovine vesicular gland microsomes. J Biol Chem 1976:
201. Miyauchi M, Ijuhin N, Nikai H, Takata T, Ito H, Ogaw a I.
Effect of exogenously applied prostaglandin E2 on al-
veolar bon e loss-histometric analysis. J Periodontol 1992:
63: 405-411.
202. Modlin RL, Nutman TB. Type 2 cytokines and negativeimmune regulation in human infections. Cun Opin Im-
munol 1993: 5: 511-517.
203. Moore MA. The clinical use of colony stimulating factors.
Annu Rev Immu nol 1991: 9: 159-191.
204. Mo reland L, Ma rgolie s G, Heck L, Saway P: Jacobs C, Beck
C, Blosch C, Kooperman W. Soluble tumor n ecrosis factor
receptor (sTNFR) results of a phase I dose-escalation
study in patients with rheumatoid arthritis. ArthritisRheum 1994: 37: S295 (abstr 813).
205. Morris AG. Interfero ns Imm unolog y 1988: l(supp1 ): 43-
45.
206. Mosmann TR. Cytokines: is there biological meaning?
Curr Opin Immunol 1991: 3: 311-314.
207. Mosmann TR, Coffman RL.TH1 an d TH2 cells: differentpatterns of lymphokine secretion lead to different func-
tional properties. Annu Rev Imm unol 1989: 7: 145-173.
208. Mosmann TR, Sad S. The expanding universe of T-cell
subsets: Thl, Th2 and more. Immunol Today 1996: 17:
138-146.
209. Mulligan R. The basic science of gene therapy Science
1993: 26 0 926-932.
210. Mundy GR. Inflammatory’mediators a nd th e destruction
of bone. J Periodont Res 1991: 2 6 213-217.
211. Nabel G, Nabel E, Yang Z, Fox BA, Plautz GE, Gao X, Hu-
ang L, Shu S, Gordon D, Chang AE. Direct gene transfer
with DNA liposome complexes in melanoma: Expression,
biologic activity and lack of toxicity in humans. Proc Natl
Acad Sci U S A 1993: 9 0 11307-11311.212. Nakashima K, Roehrich N, Cimasoni G. Osteocalcin,
prostaglandin E2 and alkaline phosphatase in gingival
crevicular fluid: their relations to periodontal status. J Clin
Periodontol 1994: 21: 327-333.
213. Nathan C, Kaplan G, Levis W, Nusrat A, Witmer M, Sher-
win S, Job C, Horowitz C, Ste inm ann R, Cohn Z. Local an d
systemic effects of intradermal recombinant interferon-
gamma in patients with lepromatous leprosy. N Engl J
Me d 1986: 315: 6-15.
214. Nell A, Matejka M, Solar P, Ulm C, Sinzinger H. Evidence
that cyclosporine inhibits periodontal prostaglandin I2
synthesis. J Periodont Res 1996: 31: 131-134.215. Nicola NA. Guidebook to cytokines and their receptors.
Oxford: Oxford University Press, 1994.216. Nienhuis A, Donahue R, Karlsson S, Clark S, Agricola B,
Antinoff N, Pierce J , f i rn er R Anderson W, Nath an D. Re-
combinant human granulocyte-macrophage colony-
stimulating factor (GM-CSF) shorte ns the p eriod of ne u-
tropenia after autologous bon e marrow transplantation in
a primate model. J Ctin Invest 1987: 80: 573-577.
217. Nish ihara T, Ohs aki Y Ueda N, Saito N, Mundy GR. Mouse
interleukin-1 receptor antagonist induced by Actino-
bacillus actinomycetemcomitans lipopolysaccharide
blocks th e effects of interleukin-1 on b one resorption a nd
osteoclast-like cell formation. Infect Immun 1994: 62:
390-397.
218. Norm an J, Franz M, Messina J, Riker A, Fabri PI, Rosem ur-
gy AS, GowerWR r. Interleukin-1 receptor antagonist de-
251: 2629-2636.
creases severity of experimental acute pancreatitis.
Surgery 1995 : 117: 648-655.
219. Offenbacher S, Farr D, Goodson J. Measurement of
prostaglandin E in crevicular fluid. J Clin Periodontol
220. Offenbacher S Odle B, Braswell L, Johnson H, Hall C,
McClure H, Orkin J, Strobert E, Green M. Changes incyclooxygenase metabolites in experimen tal periodontitis
in Macam mu la th J Periodont Res 1989: 24: 63-74.
221. Offenbacher S, Odle B, Green M, Mayambala C, Smith M,
Fritz M, van Dyke T, Yeh K, Sena E Inhibition of human
periodontal prostaglandin E2 synthesis with selected
agents. Agen ts Actions 1990: 29: 232-238.
222. Offenbacher S, Odle B, Van Dyke T. The use of crevicular
fluid prostaglandin E2 evels as a predictor of periodontal
attachment loss, J Period ont Res 1 98 6 21: 101-112.
223. Offenbacher S, Williams R, Jeffcoat M, Howell T, Odle B,
Smith M, Hall C, Johnson H, Goldhaber F? Effects of
NSAIDs on beagle crevicular cyclooxygenase metabolites
and periodontal bon e loss. J Periodont Res 1992: 27: 207-
213.224. O’Garra A. Peptide regulatory factors. Interleukins an d the
imm une system. Part 1. Lancet 19 89 1:943-946.
225. O’GarraA. Peptide regulatory factors. Interleukins a nd the
imm une system 2. Lancet 1989 1: 1003-1005.
226. Ogawa T, Kushumoto Y, Hamada S, McG hee JR, Kiyono
H. Bacteroides gingivalisspecific serum IgG and IgA sub-
class antibodies in periodontal disease. Clin Exp Immunol
227. Ogiso B, Hughes E Davies J, McCulloch A. Fibroblastic
regulation of osteoblast function by prostaglandins. Cell
Signal 1992: 4: 627-4539.
228. Ok uda K, Kato T, Na ito Y, Kikuchi Y, Takazoe I. Suscepti-
bility of Bacteroides gingivalis to bactericidal activity of
huma n s e rum. J Dent Res 1986: 65: 1024-1027.229. O ppen heim JJ, Zachariae COC, Mukaida N, Matsushima
K. Properties of the novel proinflammatory supergene
“intercrine” cytokine family. Annu Rev Immunol 1991: 9:
617-648.
230. Orange JS, Wolf SF, Biron CA.Effects of IL-12 on the re-
spon se an d susceptibility to experim ental viral infections.
J Im mu nol 1994: 152: 1253-1264.
231. Otterness IG, Bliven ML, Downs JT, Natoli EJ, Hanson DC.
Inhibition of interleukin 1 synthesis by tenidap: a new
drug for arthritis. Cytokine 1991: 3:277-283.
232. O’Sullivan M, Chilton F Huggins E, McCall C. Lipopoly-
saccharide priming of alveolar macrophages for en-
hanced sythesis of prostanoids involves induction of a
novel prostaglandin H synthase. J Biol Chem 1992: 267:
233. Page RC. The role of inflammatory mediators in the
pathogenesis of periodontal disease. J Periodont Res 1991:
2 6 230-242.
Canto r H. Differential induc -
tion of interferon gene expression after activation of
CD4+ T cells by conventional antig en and M ls supera nti-
gen. Proc Natl Acad Sci U S A 1991: 88:273G2739.
235. Payne JB, Reinhardt FIA, Masada MI: DuBois LM, Allison
AC. Gingival crevicular fluid IL-8; correlation with local
IL-1 levels and patient estrogen status. J Periodont Res
1993: 28: 451-4 53.
236. Perregaux DG, Dean D, Cro nan M. Connelly P, Gabel C A.
Inhibition of interleukin-1 beta production by SKF86002:
1981: 8: 369-367.
19 90 82: 318-325.
14547-14550.
234. Patarca R, Wei FY, Iregui
139
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 29/32
Gemmell et al.
237.
238.
239.
240.
241.
242.
243.
244.
245.
246.
247.
248.
249.
250.
251.
252.
253.
evidence of two sites of in vitro activity and of a time and
system dependence. Mol Pharrnacol 1995: 48: 433-442.
Persson GR, Engel D, Whitney C, Darveau R, Weinberg A,
Brunsvold M , Page RC. Immunization against Porphyo-
monas gingivalis inhibits progression of experimental
periodontitis in nonhuman primates. Infect Immun 1994:
62: 1026-1031.Perussia B, Chan SH, D’Andrea A, Tsuji K, Santoli D, Pos-
pisil M, Young D, Wolf SETrinchieri G. Natural killer NU
cell stimulatory factor or IL-12 has differential effects on
the proliferation of TCR-alpha beta+, TCR-gamma delta+
T lymphocytes, and NK cells. 1 lmmunol 1992: 149: 3495-
3502.
Pfeilschifter J. Transforming growth factor-p. In:Haben-
icht A, ed. Growth factors, differentiation factors, and
cytokines. Berlin: Springer-Verlag, 1990: 56-64.
Pilon M, Williams-Miller C, Cox DS. Interleukin-2 levels
in gingival crevicular fluid in periodontitis. I Dent Res
1991: 70:550 abstr 2270).
Platt D, Crosby RG, Dalbow MH. Evidence for the pres-
ence of immunoglobulins and antibodies in inflamedperiodontal tissues. J Periodontol 1970: 41: 215-222.
Podolsky DK. Inflammatory bowel disease. Part 1. N Engl
J Med 1991: 325: 928-937.
Powrie F, Coffman RL.Cytokine regulation of T-cell func-
tion: potential for therapeutic intervention. Lmmunol To-
day 1993: 14: 270-274.
Prabhu A, Michalowicz, Mathur A. Detection of local and
systemic cytokines in adult periodontitis. I Periodontol
1996: 6 7 515-522.
Punnonen 1 Aversa G, Cocks BG, McKenzie AN Menon
S, Zurawski G, de Wad Male@ R, de Vries JE. Interleukin
13 induces interleukin 4-independent IgG4 and IgE syn-
thesis and CD23 expression by human B cells. Proc Natl
Acad Sci U S A 1993:90: 3730-3734.Qwamstrijm EE, MacFarlane SA, Page RC. Effects of in-
terleukin-1 on fibroblast extracellular matrix, using a 3-
dimensional culture system. 1Cell Physiol 1989: 139: 501-
508.
Raisz LG.Physiologic and pharmacologic regulation of
bone resorption. N Engl J Med 1970 282: 909-916.
Rankin E, Choy E. Kassimos D, Kingsley GH, Sopwith A M
Isenberg DA, Panayi GS. The therapeutic effects of an en-
gineered human anti-tumour necrosis factor alpha anti-
body CDP571) in rheumatoid arthritis. Br J Rheurnatol
1995: 34: 334-342.
Re F, Mengozzi M, Muzio M, Dinarello CA,Mantovani A,
Colotta E Expression of interleukin-1 receptor antagonist
(IL- Ira) by hum an circulating polymorphonuclear cells.Eur J Immunol 1993: 23: 570-573.
Reddi K, Wilson M, Nair S, Poole S, Henderson B. Com-
parison of the pro-inflammatory cytokine-stimulating ac-
tivity of the surface-associated proteins of peri-
odontopathic bacteria. J Periodont Res 1996:31: 120-130.
Reinhardt RA Masada ME KaldahlWB, uBois LM Korn-
man KS, Choi JI, Kalkwarf KL. AUison AC. Gingival fluid
IL-1 and 1L-6 levels in refractory periodontitis. J Clin Peri-
odontol 1993:20: 225-231.
Reinhardt RA, McDonald TL, Bolton RW, Dubois LM. Kal-
dahl WB. IgG subclasses in gir~gival revicular fluid from
active versus stable periodontal sites. J Periodontol 1989:
Richards D, Rutherford RB. The effects of interleukin-1 on
60: 4-50.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
270.
collagenolytic activity and prostaglandin-E secretion by
human periodontal-ligament and gingival fibroblast. Arch
Oral Biol 1988: 33: 237-243.
Riddell S, Russer P, Greenberg P.Cytotoxic T cells specific
for CW . a potential therapy for immunocompromised
patients . Rev Infect Dis 1991: 13 suppl 11): S966S973.
Rissen R, Rahimizadeh H, Blessing E, Takeshita S, Barry Jh e r . Arterial gene transfer using pure DNA applied d i-
rectly to a hydrogel-coated angioplasty balloon. Hum
Gene Ther 1993: 4 749-758.
Rijcken M, Milller KM, Saurat J-H, Milller I, Louis JA, Cer-
ottini J-C, Hauser C. Central role for TCRlCD3 ligation in
the differentiation of CD4+ T cells toward a Thl or Th2
functional phenotype. 1 Immunoll992: 148: 47-54.
Rijcken M, Saurat JH, Hauser C. A common precursor for
CD4+ T cells producing IL-2or IL-4. J Immunol 1992: 148:
Romagnani S. Human TH1 and TH2 subsets: regulation
of differentiation and role in protection and immuno-
pathology. Int Arch Allergy Immunol 1992: 98: 279-285.
Roodman GD. Interleukin-6: an osteotropic factor? J BoneMiner Res 1992: : 475-478.
Rosa F Fellows M. Effect of gamma-interferon on MHC
antigens. Immunol Today 1984:9: 261-262.
Rosenberg S, Lotze M, Mud L, Leitman S, Chang A, Et-
tinghausen S, MatoryY,Skibber J Shiloni E, Vetto J, Seipp
C, Simpson C, Reichert C. Observations on the systemic
administration of autologous lymphokine-activated killer
cells and recombinant interleukin-2 to patients with
metastatic cancer. N Engl J Med 1985: 313 1485-1492.
Rosenkoetta M, Reder AT, Oger JJ, Antel JI?T-cell regula-
tion of polyclonally induced immunoglobulin secretion in
humans. I Immunol 1984: 132: 1779-1783.
Rossomando EF, Kennedy JE, Hadjimichael J. Tumor ne-
crosis factor alpha in gingival crevicular fluid as a possibleindicator of periodontal disease in humans. Arch Oral
Biol 1990:35: 431-434.
Rousset E Garcia E, Defrance T, Peronne C, Vezzio N, Hsu
DH, Kastelein R, MooreW anchereau J. nterleukin 10
is a potent growth and differentiation factor for activated
human B lymphocytes. Roc Natl Acad SciU S A 1992: 89:
1890-1 893.
S a f f a r J Lasfargues J. A histometric study of the effect of
indomethacin and calcitonin on bone remodelling in
hamster periodontitis. Arch Oral Biol 1984: 2 9 555-558.
Saito S, Ngan P, Saito M, Lanese R, Shanfeld J Davidovitch
Z. Interactive effects between cytokines on PGE produc-
tion by human periodontal ligament fibroblasts in vitro.
Dent Res 1990: 69: 1456-1462.Saito S, Rosol T, Saito M, N g i h P, Shanfeld J, Davidovitch
Z. Bone-resorbing activity and prostaglandin E produced
by human periodontal ligament cells in vitro. J Bone
Miner Res 1990: 5 : 1013-1018.
Saito S, Saito M, Ngan P, Lanese R, Shanfeld J Davidovitch
Z. Effects of parathyroid hormone and cytokines on
prostaglandin E synthesis and bone resorption by human
periodontal ligament fibroblasts. Arch Oral Biol 1990: 35:
845-855.
Salgame P, Abrams JS Clayberger C, Goldstein H, Convit
I , Modlin RL, Bloom BR. Differing lymphokine profiles of
functional subsets of human CD4+ and CD8+ T cell
clones. Science 1991: 254: 279-282.
Scharton Kersten T, Scott I? The role of the innate im-
1031-1036.
140
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 30/32
Cytokines an d prostagla ndins in periodontal disease~~ ______
mu ne response in T hl cell development following Leish-
mania major infection. J Leukoc Biol 1995: 57: 515-522.
271. Schen del D, Gansb acher B. Tumor-specific lysis of h u m a n
renal cell carcinomas by tumo r-infiltrating lymphocytes:
mo dulatio n of recognition throu gh retroviral transd uction
of tumour cells with interleukin 2 complementary DNA
and exogenous alpha interferon treatment. Cancer Res1993: 53: 40204025.
272. Schenk K. IgG, IgA and IgM serum antibodies against
lipopolysaccharide from Bacteroides gingivalis in peri-
odo nta l hea lth a nd disease. J Period ont Res 1985: 20: 368-
377.
273. Schenk K, Michaelsen TE. IgG subclass distribution ofserum antibodies against lipopolysaccharide from Bacter-
oidesgingivalis in periodo ntal health an d disease. APMIS
1987: 95: 41-46.
274. Schre iber S, Heinig T, Thiele HG, Raedler A. Immunoregu-
latory role of interleukin 10 in pati ents with inflammatory
bowel disease. Gastroe nterolog y 1995: 1 0 8 1434-1444.
275. Schroede r HE. Transmigration a nd infiltration of leuko-
cytes in human junctional epithelium. Acta OdontolScand 1973: 17: 6.
276. Scott €? Selective differen tiation of CD 4+ T helper cell
subsets. Curr Opin Immunol 1993: 5: 391-397.
277. Scott I: Kaufrnann SHE. The role of T-cell subsets and
cytokines in the regulation of infection. Immunol Today
1991: 12: 346-348.
278. Seibert K, a n g Y Lea hy K Hauser S, Masferrer J, Perkins
W, Lee L, Isakson I Pharmacological and biochemical
demonstration of the role of cyclooxygenase 2 in in-
flammation and pain. Proc Natl Acad Sci U S A 1994: 91:
279. Seymour GJ. Possible mech anism s involved in t he immu-
noregulation of chronic inflammatory periodontal dis-
ease. J Dent Res 1987: 66: 2-9.280. Seymour GJ. Imp ortanc e of the host response in the peri-
odontium. J Clin Periodontol 1991: 18: 421-426.
281. Seymour GJ, Cole KL, Powell RN, Lewins E, Cripps AW,
Clancy RL. Interleukin-2 production and bone resorption
activity by unstimulated lymphocytes extracted from
chronically inflamed human periodontal tissues. Arch
Oral Biol 1985: 30 481-484.
282. Seymour GJ, Gemmell E, Reinhardt RA, Eastcott J, Taub-
m a n MA. Immunopathogenes isof chronic inflammatory
periodontal disease: cellular and m olecular mechanisms.
J Periodont Res 1993: 28: 478-486.
283. Shapira L, Soskolne A, Sela M, Offenbacher S, Barak V.
The secretion of PGE2, IL-la, IL-6, and TN Fa by adhe rent
mononuclear cells from early onset periodontitis pa-tients. J Periodontol 1994: 65: 139-146.
284. Shapira L, Soskolne W, Van Dyke T. Prostag landin E2 sec-
retion, cell maturation, and CD14 expression by mono-
cyte-derived macrophages from localized juvenile peri-
odontitis patients. J Periodontol 1996: 67: 224-228.
285. Sher A, Fiorentino D, Casper P, Pearce E, Mosma nn T. Pro-duction of IL-10 by CD 4+ T lymphocytes correlates with
down-regulation of Thl cytokine synthesis in helminth
infection. J Im mu nol 1991: 147: 2713-2716.
286. She r A, Gazz inelli RT, Osw ald II? Clerici M, Kullberg M,
Pearce EJ, Berzofsky JA, Mosmann TR, James SL Morse
HC, Shearer GM. Role of T-cell derived cytokines in the
downregulation of imm une responses in parasitic and re-
troviral infection. Immunol Rev 1992: 127: 181-204.
12013-12017.
287. Simmons D, Levy D, Yannoni Y Erikson R. Identification
of a phorbol ester-repressible v-src-inducible gene. Proc
Natl Acad Sci U S A 1989: 86 11778-11782.
288. Slots I, Genco RJ. Black-pigmented Bucteroides species,
Capnocytophagaspecies, and Act ino hill us actinornyce-
temcornitans in human periodontal disease: virulence
factors in colonization survival and tissue destruction. JDe nt Res 1984: 63: 412421.
289. Smith WL,Meade EA DeWitt DL. Interactions of PGH
synthase isozymes-1 and -2 with NSAIDs. Ann N Y Acad
Sci 1994: 744: 50-57.290. Snap per CM, Paul WE. Interferon-y a nd B cell stimulatory
factor-1 reciprocally regulate Ig isotype production.
Science 1987:236 944-947.
291. Spits H, Yssel H, Takebe Y Arai N, Yokota T, Lee F Arai
K, Banchereau J, De Vries J. Recombinant interleukin 4
promotes the growth of hum an T cells. J Immunol 1987:
292. Stashenko I:Dewhirst FE, PerosW ent RL, Ago JM. Syn-
ergistic interactions between interleukin 1, tumor ne-
crosis factor, and lymphotoxin in bone resorption. Im-munol 1987: 138: 1464-1468.
293. Stashenko I:Fujiyoshie I:Obemesser MS, Prostak L, Haf-
fajee AD, Socransky SS. Levels of interleukin 1 beta in
tissue from sites of active periodontal disease. J Clin Peri-
odontol 1991: 1 8 548-554.
294. Stein SH, Hendrix CL. Interleukin-10 pro mote s anti-co lla-
gen antibody production in gingival mononuclear cells. J
Dent Res 199 6 75: 158 (abstr 1122).
295. Street NE, M osma nn TR. Functional diversity of T
lymphocytes due to secretion of different cytokine pat-
terns. FASEB 1 1991: 5: 171-177.
296. Suzuki JB, Risom L, Falkler WA Jr, Collison C, Bowers G.
Effect of periodontal therapy on spontaneous lymphocyte
response and neutrophil chemotaxis in localized an d gen-eralized juvenile periodontitis patients. 1Clin Periodontol
1985 12: 124-134.
297. Sym ons JA, Young PR, DuffGW. Soluble type U interleukin
1 (IL-1) receptor bin ds a nd blocks p rocessing of IL-1 beta
precursor an d loses affinity for IL-1 receptor antagonist.
Proc Natl Acad Sci U S A 1995: 92: 1714-1718.
298. Takahashi K, Takashiba S Nagai A, Takigawa M, Myoukai
E Kurihara H, Murayama Y.Assessment of interleukin-6
in the pathogenesis of periodontal disease. 1 Periodontol
299. Takeichi 0, Taubman MA, Haber J, Smith DJ, Moro I.
Cytokine profiles of CD4 and CD8 T cells isolated from
adult periodontitis gingivae. J Dent Res 1994: 73: 205
(abstr 1549).300. Takigawa M, Takashiba S, Takahashi K, Arai H, Kurihara
H, Murayama Y. Prostaglandin E2 inhibits interleukin-6
release but not transcription in human gingival fibro-
blasts stimulated wth interleukin-lp or tumor necrosis
factor-a. J Period ontol 1994: 65: 1122-1127.
301. Tanaka K, Aikawa Y, Kawasaki H. Asaoka K, Inaba T,Yoshida C. Pharmacological studies on 3-formylamino-
7 -methylsulfonylamino- 6-phenoxy-4H 1 benzopyran-4 -on e (T-6141, a novel antiinflammatory agent. 4th com-
munication: inhibitory effect on the production of in-
terleukin-1 and interleukin-6. J Pharmacobiodyn 1992:
15: 649-655.
302. Tanaka K, Makino S, Shimotori T, Aikawa Y, Inaba T, Yosh-
ida C. Pharmacological studies of the new antiinflamma-
139: 1142-1 147.
1994: 65: 147-153.
141
8/12/2019 Cytokines and Prostaglandins in Immune Homeostasis and Tissue Destruction in Periodontal Disease
http://slidepdf.com/reader/full/cytokines-and-prostaglandins-in-immune-homeostasis-and-tissue-destruction-in 31/32
Gemmell et al
tory agent 3-formylamino-7-methyIsulfonylamino-6-
phenoxy-4'-l-benzopyran-4-one:ffect on the arachidon-
ic acid cascades. Arzneimittelforschung 1992: 42: 945-950.
303. Taubman MA, Stoufi ED, Ebersole IL Smith DI. Pheno-
typic studies of cells from periodontal disease tissue. l
Periodont Res 1984: 19: 587-590.
304. Tepper RI, Coffman RL, Leder F A n eosinophil-dependent
305.
306.
307.
308.
309.
310.
311.
312.
313.
314.
315.
316.
317.
318.
319.
.mechanism for the antitumour effect of interleukin-4.
Science 1992: 257: 548-551.
Te Velde AA, Huijbens RJ, Heije K de Vries JE , Figdor CG.
Interleukin-4 (IL-4) inhibits secretion of IL- 1 beta, tumor
necrosis factor alpha, and 1L-6 by human monocytes.
Tew JG, Engel D, Mangan D. Polyclonal B-cell activation
in periodontitis. 1 Periodont Res 1989: 24: 225-241.
Thomson BN, Mundy GR, Chambers TI. Tumor necrosis
factors alpha and beta induce osteoblastic bone resorp-
tion. J Immunol 1987: 138: 775-779.
Tokoro Y Yamamoto T, Hara K. IL-ls mRNA as the pre-
dominant inflammatory cytokine transcript: correlation
with inflammatory cell infiltration into human gingiva. IOral Pathol Med 1996: 25: 225-231.
Tonetti MS, Freiburghaus K. Lang NE Bickel M. Detection
of IL-8 and matrix metalloproteinase transcripts in
healthy and diseased gingival biopsies by RNAIPCR. J
Periodont Res 1993: 28: 511-513.
Tonetti MS, lmboden MA, Gerber L, Lang N E Laissue 1
Mueller C. Localized expression of mRNA for phagocyte-
specific chemotactic cytokines in human periodontal in-
fections. Infect Immun 1994: 62: 4005-4014.
Trinchieri G. Interleukin-12 an d its role in the generation
of Thl cells. Immunol Today 1993: 14: 335-337.
Trinchieri G, Perussia B. Immune interferon: a pleiotropic
lymphokine with multiple effects. Immunol Today 1985:
Van Dyke TE, Bartholomew E, Genco RJ, Slots J Levine
MJ. Inhibition of neutrophil chernotaxis by soluble bac-
terial factors. 1 Periodontol 1982: 53: 502-508.
Van Dyke TE, Lester MA, Shapira L. The role of the host
response in periodontal disease progression: implications
for future treatment strategies. I Periodontol 1993:
64(suppl): 792-806.
Vane J Bottling R. Mechanism of action of anti-inflam-
matory drugs. Scand J Rheumatol 1996: 25(suppl 102): 9-
21.
Vogel R Schneider L, Goteiner D. The effects of a topi-
cally-active non-steroidal anti-inflammatory drug on liga-
ture-induced periodontal disease in the squirrel monkey.
J Clin Periodontol 1986: 13: 139-144.Wagner E, Cotten M, Foisner R, Birnstiel M. Transferrin-
polycation-DNA complexes: the effect of poly-cations on
the structure of the complex and DNA delivery to cells.
Proc Natl Acad Sci U S A 1991: 88: 4255-4259.
Wallner BE Mattaliano R J Hession C, Cate RL,Tizard R
Sinclair LK Foeller C, Chow EB Browning JL, Ramachand-
ran KL, Pepinsky RB. Cloning and expression of human
lipocortin, a phospholipase A2 inhibitor with potent anti-
inflammatory activity. Nature 1986: 320: 77-81.
Walsh LJ, Stritzel E Yamazaki K, Bud PS, Gemmell E,
Seymour GI. Interleukin-1 and interleukin-1 inhibitor
production by human adherent cells stimulated with
periodontopathic bacteria. Arch Oral Biol 1989: 34: 679-
683.
Blood 1990: 76: 1392-1397.
6: 131-136.
320. Wendling D, Racadot E, Wijdenes I. Treatment of severe
321.
322.
323.
324.
325.
326.
327.
328.
329.
330
331
332.
333.
334.
335.
rheumatoid arthri tis by anti-interleukin 6 monoclonal
antibody. J Rheumatol 19 93 2 0 259-262.
Whitney C, Ant J, Moncla B, Johnson B, Page RC, Engel
D. Serum immunoglobulin G antibody to Porphyromonus
gingivulis in rapidly progressive periodontitis: titer, avid-
ity, and subclass distribution. Infect Immun 1992: 60:
Wdiams R, Jeffcoat M, Howell T, Rolla A, Stubbs, Teoh
K, Reddy M , Goldhaber l? Altering the progression of
human alveolar bone loss with the non-steroidal anti-
inflammatory drug flurbiprofen. J Periodontol 1989: 60:
485-490.
Williams TJ, Peck MJ. Role of prostaglandin-mediated
vasodilation in inflammation. Nature 1977: 270: 530-532.
Wills D, Maneval E Menzel M, Harris ME Sutjipto S, Vail-
lancourt MT. Huang WM, Johnson DE, Anderson SC, Wen
SE Bookstein R, Shapard H, Gregory R.Development and
characterization of recombinant adenovirus encoding hu -
man p53 for gene therapy of cancer. Hum Gene Ther
1994: 5: 1079-1088.Wilson M, Kamin S, Harvey W Bone resorbing activity of
purified capsular material from Actinobucillus actino-
mycetemcomitans. J Periodont Res 1985: 20: 484491.
Winning T, Gemmell E, Polak B, Savage NW, Walsh LW,
Seymour GI. Expression of CDla on monocytes cultured
with supernatants from periodontally diseased gingival
epithelial cells. Oral Dis 1996 2: 247-252.
WOW1 Malone R Williams P, Chong W, Acsadi G, Jani A,
Felgner PL. Direct gene transfer into mouse muscle in
vivo. Science 1990: 247: 1465-1468.
Xu Amano J, Aicher WK, TaguchiT Kiyono H, McGhee JR .
Selective induction of Th2 cells in murine Peyer's patches
by oral immunisation. Int Immunol 1992: 4 433-445.
Xu Amano I, Kiyono H, Jackson RJ, Staats HE Fujihashi KBurrows PD, Elson CO, Pillai S, McGhee JR. Helper T cell
subsets for immunoglobulin A responses: oral immunis-
ation with tetanus toxoid and cholera toxin as adjuvant
selectively induces Th2 cells in mucosa associated tissues.
1 Exp Med 1993: 178: 1309-1320.
Yamamoto M, Fujihashi K, Hiroi T,McGhee JR, Van Dyke
TE, Kiyono H . Molecular and cellular mechanisms for
periodontal diseases: role of Thl and Th2 type cytokines
in induction of mucosal inflammation. 1 Periodont Res
Yamashita K , Eastcott JW aubman MA, Smith DI, Cox
DS. Effect of adoptive transfer of cloned Actinobucillus
uctinomycetemcorniturisspecificT helper cells on peri-
odontal disease. Infect Immun 1991: 59: 1529-1534.Yamazaki K Nakajima T, AoyagiT,Hara K. Immunohistol-
ogical analysis of memory T lymphocytes an d activated B
lymphocytes in tissues with periodontal disease. J Peri-
odont Res 1994: 28: 324-334.
Yamazaki K, Nakajima T, Hara K . Immunohistological
analysis of T cell functional subsets in chronic inflamma-
tory periodontal disease. Clin Exp Immunol 1995: 99:
384-39 1.
Yamazaki K, Polak B. Bird PS, Gemmell E, Hara K,
Seymour GI. Effects of periodontopathic bacteria on IL-
1 and IL-I inhibitor production by human polymorpho-
nuclear neutrophils. Oral Microbiol Immunol 1989: 4:
Yavuzyilmaz E, Yamalik N , Bulut S, Ozen S, Ersoy E Saatqi
2194-2200.
1997: 32: 115-119.
193-198.
142
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Cytokines and prostaglandins in periodontal disease
genase-2 mRNA in human gingival fibroblasts. Inflam-
mation 1995: 19: 549-560.
337. Zurawski G, de Vries JE. Interleukin 13, an interleukin 4-
like cytokine that acts on monocytes and B cells, but not
on T cells. Immunol Today 1994: 15: 19-26.
0.The gingival crevicular fluid interleukin-lp and tumour
necrosis factor-a levels in patients with rapidly progress-
ive periodontitis.Aus Dent J 1995:40: 46-49.
336. Yucel-Lindberg T, Ahola H, Nilsson S , Carlstedt-DukeJ
Modeer T. Interleukin-10 induces expressionof cyclooxy-
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