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Placenta (2003), 24, Supplement A, Trophoblast Research, Vol. 17, S33–S46doi:10.1053/plac.2002.0948

Cytokines, Prostaglandins and Parturition—A Review

J. A. Keelana, M. Blumenstein, R. J. A. Helliwell, T. A. Sato, K. W. Marvin and M. D. Mitchell

Liggins Institute, University of Auckland, 2–6 Park Ave, Grafton, Auckland, New ZealandPaper accepted 30 December 2002

The elaboration of cytokines, chemokines and immunomodulatory proteins in the placenta and gestational membranes has been

extensively investigated in the context of both normal and abnormal pregnancy and delivery. Patterns of expression of cytokines

in the foetal membranes and decidua suggest that inflammatory activation occurs modestly with term labour, but much more

robustly in preterm delivery, particularly in the presence of intrauterine infection. Enhanced chemokine expression, particularly

evident in deliveries with an infected amniotic cavity, is presumably responsible for recruiting infiltrating leukocytes into the

membranes thereby amplifying the inflammatory process and hastening membrane rupture and delivery. Anti-inflammatory

cytokines suppress inflammatory reactions in the placenta, but under some circumstances may act in a pro-inflammatory fashion

in the membranes. Intracellular signalling by cytokines is modulated by proteins such as SOCS (Silencer Of Cytokine

Signalling)-1, -2 and -3. Changes in the abundance of these proteins occur with term labour, implicating them as modulators of cytokine actions around the time of parturition. Prostaglandins, released by the membranes in response to stretch and the actions

of pro-inflammatory cytokines, act not only upon the myometrium and cervix, but may also exert paracrine/autocrine eff ects on

cell viability and matrix protein integrity. The localization and regulation of prostanoid isomerases, responsible for converting

PGH2 (derived from prostaglandin H synthase-1 and -2) to bioactive prostanoids, are being studied in these tissues, particularly

in the context of cytokine interactions. Although the gestational tissues are known to be sources of PGD2, PGJ2 and its derivatives,

the regulation of production of these prostaglandins has yet to be studied in any detail and their actions, which may include

apoptosis and suppression of inflammation, remain poorly defined. A more complete understanding of these aspects of

cytokine-prostaglandin interactions in pregnancy and parturition will, no doubt, unfold as current studies come to fruition.

2003 IFPA and Elsevier Science Ltd. All rights reserved.

Placenta (2003), 24, Supplement A, Trophoblast Research, Vol. 17, S33–S46

INTRODUCTION

While our understanding of some aspects of human parturition

is reasonably thorough, the complexity of interactions between

various endocrine and paracrine factors, issues relating to

anatomical regionality and tissue specialization, and diff erences

between normal and pathological deliveries have thwarted our

attempts to develop a complete and unambiguous appreciation

of what determines the timing of birth and the role(s) played

by the various intrauterine tissues and organs in this process

(Keelan, Myatt and Mitchell, 1997; Challis et al., 2000).

Inter-species diff erences and limitations in the suitability

of animal models further complicate research in this area.

Nevertheless, there is widely accepted evidence that prosta-

glandin production is a key player in the parturient process at

term, and preterm in the presence of intrauterine infection

(Mitchell et al., 1995; Gibb, 1998; Kniss, 1999). Similarly,

following studies that began in the early 1980s elucidating the

role of local pro-inflammatory cytokine production in the

pathophysiology of preterm labour, there is now strong data

that increased intrauterine cytokine production is associated

with both term and preterm labour and is involved in a number

of key aspects of parturition (Gibbs et al., 1992; Dudley, 1997;

Gomez et al., 1997). The interactions between cytokines and

prostaglandins and their importance to human parturition are

the focus of this review.

CYTOKINE PRODUCTION BY GESTATIONALTISSUES WITH TERM AND PRETERM LABOUR

The placenta and extraplacental membranes (gestational tis-

sues) are sources of a large number of cytokines, chemokines

and related factors (reviewed by Bowen et al., 2002a,b). Recent

cDNA array studies carried out in our laboratory have high-

lighted the diversity and extent of cytokine expression in the

amnion and choriodecidua (Table 1) and identified clusters of

inflammation-associated genes upregulated with labour both at

term and preterm (Marvin et al., 2002a). These studies showed

that, while many cytokines/chemokines are expressed in these

a To whom correspondence should be addressed at: Liggins Institute,University of Auckland Faculty of Medical and Health Sciences, 2–6Park Ave, Grafton, Auckland, New Zealand. Fax: +64-9-373-7497;E-mail: [email protected]

0143–4004/03/$-see front matter 2003 IFPA and Elsevier Science Ltd. All rights reserved.



Table 1. Relative expression of cytokine and chemokine genes in amnion and choriodecidual membranes determinedby cDNA array analysis in four gestational groups (median, n=4 per group): term not in labour (TNL), termfollowing spontaneous labour (TSL), preterm labour without intrauterine infection (PTL) and preterm labour withchorioamnionitis (PTL+). Genes with no detectable signal are not listed. Hybridization intensity was adjusted forbackground and normalised to the average signal from nine housekeeping genes (see Marvin et al., 2002a formethodologic details). Shading intensity represents fold increase (or decrease) compared to signal in TNL samples

(where non-detectable, a value of 1 was assigned); 5–10 fold; 10–50 fold; 50–100 fold; >100 fold diff erence.

Gene

Amnion Choriodecidua

TNL TSL PTL PTL+ TNL TSL PTL PTL+

CXC ( ) chemokinesENA-78 9.1 10.6 55.3 204.6 9.3 13.4 18.4 104.5GRO- 1.9 24.5 62.9 387.1 0.7 1.4 17.7 185.1GRO- 2.0 28.4 77.5 454.0 0.3 2.4 30.6 207.4GRO- 23.4 48.0 131.0 544.1 24.5 32.3 56.8 230.5IL-8 0 78.6 83.6 4738 0 8.5 63.2 1470IP-10 1.4 4.7 13.2 12.1 8.0 6.0 6.6 13.5

CC ( ) chemokines6Ckine 0 0 0 0 14.9 2.6 2.5 4.2Eotaxin-1 0 0 7.3 7.1 0 0 0 7.1Eotaxin-2 0 0 2.1 0 0 3.9 2.3 7.0

HCC-1 0 0 0 3.8 0 0 1.8 12.5I-309 0 0 0 251.5 0 0 0 7.8MCP-1 4.0 11.1 56.7 120.2 10.6 7.2 19.1 198.1MCP-2 0 0 0 16.2 2.0 0 2.8 35.4MIP-1 0 5.3 19.8 243.7 0 0.9 13.7 61.7MIP-1 0 4.9 26.5 285.9 1.9 2.4 22.5 90.4MIP-3 3.8 8.8 18.3 244.3 0 0 0 60.2MIP-1 0 0 2.4 21.2 0 0 0 9.7MPIF-1 9.2 13.7 65.8 44.8 18.8 29.2 32.5 21.1PARC 2.5 1.2 14.4 41.9 38.6 8.3 10.8 113.2RANTES 0 0 0 11.8 1.3 0 4.0 13.8

-chemokines/othersLymphotctin 1.5 0.9 0 4.7 2.6 6.2 1.6 14.1Fractalkine 15.8 19.5 46.4 84.3 13.4 21.6 10.4 27.0Midkine 21.3 16.6 39.6 39.5 78.7 50.1 44.5 113.1

MIF 225.5 243.2 323.8 263.4 193.8 252.4 223.2 181.0Pleiotrophin 2.5 0.0 22.1 0.0 37.8 84.8 53.5 19.2PREF-1 171.8 152.4 394.1 149.3 104.5 188.4 99.8 60.2

CytokinesIL-1 15.7 31.3 64.7 187.8 17.2 29.3 35.5 90.4IL-1 18.2 11.1 45.7 1132 125.2 95.1 99.1 854.3IL-6 0 3.0 2.7 48.5 0 7.6 17.9 41.6IL-10 0 0 0 0 0 0 0 4.0IL-11 12.9 21.6 35.3 27.5 8.2 28.6 14.4 17.2IL-12p35 1.6 0.9 0 1.3 0 15.4 3.5 11.9IL-16 33.1 32.6 82.0 100.2 27.4 47.5 76.7 70.3PBEF 33.3 238.3 129.9 1498 35.8 108.4 126.4 1587Flt-3 Ligand 13.0 10.2 17.4 24.9 20.6 12.0 5.1 15.0MSP 5.8 10.6 18.1 9.4 4.8 9.6 0 9.5IK 90.4 111.8 470.7 147.4 89.0 121.7 98.5 56.3

G-CSF 0 15.2 55.6 102.1 0 2.6 10.9 88.1GM-CSF 5.2 3.8 26.8 40.1 6.7 13.3 19.4 26.0LIF 0 1.5 0 0 0 0 0 4.6Oncostatin M 12.4 17.8 92.5 355.6 6.0 20.8 19.1 65.8ST2 0 20.2 121.9 31.8 202.7 313.5 416.3 147.8

TGF- superfamilyTGF-1 17.1 35.4 37.5 32.4 42.2 45.7 24.6 40.2Activin A 32.3 23.8 67.3 34.3 52.5 205.5 128.2 90.3Inhibin- 32.3 16.3 683.1 217.1 183.3 198.6 80.9 40.2MIC-1/pTGF- 46.5 45.6 91.1 59.6 62.7 125.6 87.3 52.5BMP-2 28.7 51.7 130.3 87.8 28.8 40.3 45.0 48.6BMP-3 19.1 30.6 11.1 10.8 17.7 9.6 0 1.4BMP-6 352.5 240.4 629.3 965.9 305.2 318.5 375.4 304.8

S34 Placenta (2003), Vol. 24, Supplement A, Trophoblast Research, Vol. 17



tissues before labour, normal term labour is associated with

only a modest upregulation of their expression. The extent of

inflammatory activation that occurs with normal term labour is

a subject of some debate, and these data would suggest that itis not robust. In contrast, dramatically elevated expression of a

number of genes, particularly those of the chemokine class, was

observed in the gestational membranes in preterm deliveries

complicated by chorioamnionitis. Since these tissues are infil-

trated with leukocytes this finding is hardly surprising, yet

interestingly chemokine expression was also elevated in mem-

branes delivered with preterm labour that had no evidence of

intrauterine infection or inflammation compared to those

delivered by normal term labour (Table 1). These data are

consistent with measurements of chemokine proteins. For

example, interleukin (IL)-8 concentrations in amniotic fluid

not only increase from early pregnancy to term but increasemarkedly with the onset of spontaneous term labour (Saito et

al., 1993). Levels of IL-8 in the lower uterine segment are also

elevated with labour (Osmers et al., 1995b). Concentrations of

RANTES (regulated on activation, normal T-cell expressed

and secreted) in amniotic fluid increase with the onset of term

labour (Athayde et al., 1999), although chemokines GRO-

(growth-related oncogene) and IL-16 do not (Cohen et al.,

1996; Athayde et al., 2000). In contrast, levels of these

cytokines in amniotic fluid from preterm deliveries with

intrauterine infection are markedly elevated (Athayde et al.,

1999, 2000). These findings raise the interesting question as to

the nature of the initiating signal that triggers increased

chemokine production in the membranes of ‘non-infected’

preterm deliveries. We speculate that a ‘trivial’ or incidental

pathogenic exposure may elicit an inappropriately robustimmune response in some women that fails to resolve and

commences a feed-forward inflammatory loop, triggering

parturition.

Many other cytokine genes found in the arrays to be

increased with preterm labour have been studied previously

at both the mRNA and protein level; examples include IL-

1, IL-6, tumour necrosis factor (TNF)-, granuclocyte-

macrophage colony-stimulating factor (GM-CSF), granulocyte

colony stimulating factor (G-CSF) and leukaemia inhibitory

factor (LIF). Exposure to labour at term results in increases

in IL-1 production by the placenta, amnion, choriodecidua,

and unseparated foetal membranes; expression of IL-1 andTNF- mRNA is also increased with labour in the amnion,

chorion, and isolated decidua (see Bowen et al., 2002b). The

onset of labour at term induces elevations in amniotic fluid

concentrations of IL-1, IL-6 and TNF-. Amniotic fluid

concentrations of GM-CSF increase with labour, as do con-

centrations of G-CSF. LIF is undetectable in amniotic fluid of

normal pregnancy at midtrimester and at term, but is observed

in amniotic fluid following the onset of labour. Levels of

TNF-, IL-1 and IL-6 in amniotic fluid are also elevated in

preterm deliveries with microbial invasion of the amniotic

cavity, while numerous in vitro studies have demonstrated the

Table 1. Continued

Gene

Amnion Choriodecidua

TNL TSL PTL PTL+ TNL TSL PTL PTL+

TGF- superfamily continuedBMP-7 21.7 34.6 38.0 47.1 16.4 24.8 22.8 29.0

BMP-8 0 0 7.6 0 17.4 7.5 0.8 9.1EBAF/TGF-4 8.9 11.0 26.0 8.4 15.7 20.3 20.0 16.8TNF- superfamily/apoptosis

TNF- (317) 3.4 18.7 64.3 4.4 4.1 0 33.0TRAIL 0 8.0 37.3 1.3 189.5 286.6 115.7 69.9TWEAK 26.7 26.5 50.0 22.0 25.5 21.8 6.1 18.0April 1.1 6.6 4.1 4.1 6.2 3.6 2.1 14.8FasL 16.0 0.7 12.1 8.2 1.0 5.6 0.0 4.4LIGHT/TNFSF-14 11.7 8.6 19.2 25.1 4.2 9.6 0.6 28.1LT- 39.5 20.1 47.9 62.3 22.5 30.6 40.0 56.1OX40L 36.9 1.4 10.9 19.4 0 5.7 2.7 13.4TOSO 5.8 1.5 5.7 7.5 1.2 2.5 3.6 7.7PP14 24.0 1.9 17.6 21.3 72.5 15.4 28.4 1078SARP-1 5.1 7.0 20.9 14.4 13.3 13.9 15.3 13.8SARP-3 42.8 30.3 86.9 161.4 38.9 43.5 49.9 47.5

Abbreviations: IP-10, interferon-inducible protein-10; ENA-78 , epithelial cell-derived neutrophil activating peptide-78; HCC-1,human CC chemokine-1; MIP-1, macrophage inhibitory protein-1; MCP , macrophage chemotactic protein; MPIF-1, myeloidprogenitor inhibitory factor-1; PARC , pulmonary and activation-regulated chemokine; MIF , macrophage inhibitory factor, PREF-1,pre-adipocyte factor-1; IL, interleukin; PBEF , pre-B cell colony enhancing factor; IK , interferon inhibitory cytokine; MSP ,macrophage stimulating protein; G-CSF , granulocyte colony stimulating factor; GM-CSF , granulocyte macrophage colonystimulating factor; LIF , leukemia inhibitory factor; TGF- , transforming growth factor-beta; MIC-1, macrophage inhibitorycytokine-1; BMP , bone morphogenic protein; EBAF , endometrial bleeding-associated factor; TNF-, tumour necrosis factor-alpha;TRAIL, TNF-related apoptosis inducing ligand; TWEAK , TNF-related weak inducer of apoptosis; APRIL, a proliferation-inducedligand; LT- , lymphotoxin-beta; PP14, placental protein 14; SARP , secreted apoptosis-related protein.

Keelan et al.: Cytokines, Prostaglandins and Parturition S35



ability of the amnion, chorion and decidua to release cytokinesupon stimulation with either LPS or IL-1/TNF- (Bowen

et al., 2002b). In cervicovaginal fluids, TNF-, IL-1, IL-6

and IL-8 can be detected before labour onset, particularly in

women who deliver preterm with associated intraamniotic

infection (Inglis et al., 1994; Rizzo et al., 1996, 1998;

Mattsby-baltzer et al., 1998). Concentrations of inflammatory

cytokines in cervicovaginal secretions increase during spon-

taneous term labour (Cox et al., 1993; Tanaka et al., 1998),

peaking at the time of maximal cervical dilation.

Our earlier data on cytokine levels in tissue extracts from

term and preterm deliveries showed that IL-1, IL-6 and IL-8

concentrations in the extraplacental membranes are modestlyelevated with spontaneous term labour, but are dramatically

elevated in preterm deliveries (Keelan et al., 1999c) (Figure

1A). In the tissues from preterm deliveries (with and without

intrauterine infection), cytokine levels correlate with extent of

leukocyte infiltration (Figure 1B). Leukocytes which are abun-

dant in the majority of tissues from microbiologically con-

firmed infection-positive pregnancies, have been shown to be

activated in infection-associated preterm deliveries. The

association between high cytokine concentrations in amniotic

fluid and pregnancies complicated by premature rupture of

membranes (PROM) is particularly strong when infection is

present (as confirmed by microbiological culture of the amni-

otic fluid), suggestive of a strong link between the host

response to infection and onset of preterm labour (Romero

et al., 1988, 1993). The primary cellular source of cytokine

production in the presence of intrauterine infection is, there-

fore, likely to be leukocytes that are recruited into the

gestational membranes to fight the pathogen. This supposition

is supported by recent imunohistochemical evidence thatleukocytes are the predominant sites of staining for IL-1 in

myometrium, cervix and decidual stromal cells, although in the

foetal membranes IL-6 and TNF- immunostaining was also

present in decidual stromal cells and chorionic trophoblast, in

addition to leukocytes (Young et al., 2002). Low levels of

cytokine/chemokine expression have been reported in non-

inflamed tissues, supporting data demonstrating low but

detectable levels of cytokine production by gestational mem-

branes in the absence of inflammatory stimuli. Interestingly,

evidence of NF-B activation in the decidua of membranes

from preterm deliveries with no evidence of infection has been

reported recently (Yan, Sun and Gibb, 2002), consistent with

other evidence discussed above of inflammatory activation

being part of the pathophysiology of non infection-associated

preterm delivery.

In contrast to the increase in cytokine production observed

in foetal membranes and decidua during parturition, reports of

cytokine changes in the villous placenta during term or

preterm labour are less consistent. Elevated maternal serum

IL-6 concentrations have been reported to be diagnostic for

intrauterine infection-associated preterm labour, providing

indirect evidence of a placental involvement in some instances

of infection-driven preterm deliveries. A decidual, or even

cervical, source of the cytokine cannot be discounted, however.

Studies of placental cells and tissue in vitro have demonstratedtheir ability to respond to inflammatory stimuli such as

pathogenic bacteria, LPS or IL-1 with increased production

of cytokines (IL-1, IL-6, IL-10), chemokines (macrophage

chemotactic protein-1, IL-8) and prostanoids (PGE2) (Denison

et al., 1998; Goodwin et al., 1998; Griesinger et al., 2001).

Interestingly, the response in terms of immunomodulator

production of the term placenta/trophoblast to TNF- is very

weak (Goodwin et al., 1998; Pomini, Caruso and Challis, 1999;

Agarwal et al., 2000). These data suggest that the capacity of

the placenta to partake in the inflammatory process does exist.

Whether or not this occurs in pregnancy in the absence of

placental infection remains to be determined.

ANTI-INFLAMMATORY CYTOKINES AND

PARTURITION

In addition to proinflammatory cytokines, gestational tissues

also produce anti-inflammatory cytokines such as IL-10

(Cassatella et al., 1993; Trautman et al., 1997; Denison et al.,

1998). Endogenous IL-10 produced within the choriodecidua

in response to LPS ameliorates the release of TNF- and

production of PGE2 (Sato et al., 2003). IL-10 production by

Figure 1. (A) Cytokine abundance in amnion from pregnancies delivered atterm before onset of labour (TNL), term following spontaneous labour (TSL),and preterm delivery (PTL). Median values are shown (n=15 term; n=29preterm)interquartile range. Diff erences between TSL and TNL, and PTLand TSL, were statistically significant (P<0.05) for all three cytokines. Dataderived from Keelan et al. (1999a). (B) Correlation between tissue cytokineconcentrations (meansd) and leukocyte infiltration in amnion from preg-nancies delivered preterm. Leukocyte infiltration on full thickness membraneswas determined using immunohistochemistry (anti-CD45) and scored similarto that described by Salafia, Weigl and Silberman (1989). A score of 0 indicatesno leukocyte infiltration of the fetal membranes, while a score of 4 is indicativeof severe chorioamnionitis. Sample size (n) indicated in parentheses.




decidual cells in vitro increases upon treatment with IL-1 and

bacterial cell wall products (Roth et al., 1996; Dudley et al.,

1997a; Jones, Finlay-Jones and Hart, 1997; Paradowska,

Blacholszewska and Gejdel, 1997) and has been detected in the

amniotic fluid of women during late gestation (Greig et al.,

1995; Dudley et al., 1997b). Although the data are unclear as to

the role of IL-10 in the setting of premature labour with

intrauterine infection, it has been reported that treatment withIL-10 prevents LPS-induced preterm delivery in rats (Terrone

et al., 2001). A withdrawal of anti-inflammatory cytokine

actions during labour might be anticipated to facilitate inflam-

matory processes associated with parturition. In the term

placenta, levels of IL-10 expression have been reported to

decline prior to labour, and remain low through labour (Hanna

et al., 2000). While exposure to labour has been reported to

decrease secretion of IL-10 from choriodecidua (Simpson,

Keelan and Mitchell, 1998), others have reported no change

with labour in amniotic fluid IL-10 levels (Greig et al., 1995;

Dudley et al., 1997b; Jones, Finlay-Jones and Hart, 1997) or in

decidual IL-10 production ( Jones, Finlay-Jones and Hart,

1997). IL-10 inhibits cytokine and PG production by human

chorion, decidual and placental cells in vitro (Barsig et al.,

1995; Spencer et al., 1995; Fortunato et al., 1996; Trautman

et al., 1996; Fortunato, Menon and Lombardi, 1997), as well as

LPS-stimulated PGE2 production by intact foetal membranes

(Wang et al., 1995). Interestingly, the placenta has recently

been reported to be a source of a soluble IL-22 receptor (Xu

et al., 2001). Since IL-22, a member of the IL-10 family, has

pro-inflammatory actions, the presence of this soluble receptor

in placenta suggests it may serve a protective function. Even

more intriguingly, a novel spliced mRNA coding for a soluble

IL-10 receptor has been described which is expressed ONLY

in the placenta (Gruenberg et al., 2001). The function of thisreceptor and changes in its expression during pregnancy and

labour remains to be determined.

IL-4, another anti-inflammatory cytokine, decreases prosta-

glandin production from decidual cells while increasing pro-

duction of IL-1RA (Bry and Hallman, 1992), and decreases

inflammatory cytokine-stimulated prostaglandin production by

placenta/trophoblast cultures. However, amniotic fluid IL-4

concentrations do not show a consistent increase following

normal term labour (Dudley et al., 1996). IL-1 receptor

antagonist (IL-1RA) is present in extremely high concen-

trations in amniotic fluid in mid to late gestation, but there is

no evidence of a change associated with parturition (Romeroet al., 1992). Decidual IL-1RA expression is similarly un-

aff ected by labour (Ammala et al., 1997), as are cord blood

levels (Hata et al., 1996). Only maternal plasma levels of

IL-1RA have been reported to be elevated with labour

(Austgulen et al., 1994). TGF-1 decreases basal and cytokine-

stimulated prostaglandin production from amnion and

decidual cells (Berchuck et al., 1989; Bry and Lappalainen,

1994), while IL-1RA and TGF-1 both suppress IL-1-induced

PG production in the myometrium (Todd et al., 1996).

TGF- and the related molecule macrophage inhibitory

cytokine (MIC)-1 are present in amniotic fluid at term but

changes in their concentrations with parturition have not yet

been reported (Lang and Searle, 1994; Moore et al., 2000).

Preliminary data from our laboratory indicates that the

amnion, chorion and decidua are sources of MIC-1, but labour

is not associated with changes in amniotic fluid levels of

MIC-1.

These cytokines, which typically act as anti-inflammatory

factors, have been reported to exert unusual stimulatory eff ectsin term gestational tissues. Both IL-4 and IL-10 have been

reported to stimulate the release of prostaglandins and inflam-

matory cytokines within gestational tissues (Adamson et al.,

1993, 1994; Simpson, Keelan and Mitchell, 1999). Although

IL-10 inhibits PGE2 production by intact foetal membranes,

its eff ects on PGE2 and IL-6 production by amnion explants

are stimulatory (Keelan et al., 1997). Similarly, IL-1RA has

been found to increase prostaglandin production by decidual

cells, the opposite of its actions in almost all other tissues

(Mitchell et al., 1993). This has led to the hypothesis that

term labour is associated with a withdrawal or reversal of

anti-inflammatory agents as part of an evolutionary adap-

tation to accelerate inflammatory processes necessary for

successful labour and delivery (Simpson, Keelan and

Mitchell, 1998).

CYTOKINE SIGNALLING IN PLACENTAL

TISSUES WITH PARTURITION

Cytokines activate several intracellular signalling pathways in

order to exert their physiological eff ects. The receptors for

several significant pro- and anti-inflammatory cytokines bind

to members of the JAK family of tyrosine kinases and activate

downstream STAT signalling (Imada and Leonard, 2000). Inrecent years it has become increasingly evident that signalling

exerted by cytokines are negatively controlled by a variety of

factors (reviewed by Krebs and Hilton, 2001). A novel family

of suppressors of cytokine signalling (SOCS) proteins was

discovered in 1997 and are the subject of several recent reviews

(Nicola and Greenhalgh, 2000; Krebs and Hilton, 2001;

Alexander, 2002). SOCS proteins act as intracellular regulators

of cytokine signalling by binding to members of the JAK

family, inhibiting kinase activity as well as subsequent phos-

phorylation and activation of downstream targets. The SOCS

proteins inhibit signalling by a wide range of cytokines and

related factors including LIF, IL-6, IL-4, prolactin, growthhormone, interferons and stem cell factor. Negative regulation

of intracellular signalling by SOCS proteins may play a crucial

role in both normal and disease states by, for example,

terminating responses to potentially damaging eff ects of

cytokine action in inflammatory responses. SOCS1 null mice

exhibit fatal, immune-mediated inflammatory disease (Zhang

et al., 2001; Metcalf et al., 2002), while SOCS2 has been

identified as an essential negative regulator of growth hormone

and insulin-like growth factor I signalling (Metcalf et al.,

2000). Interestingly, SOCS3 knock out mice exhibited embry-

onic lethality and placental defects indicating a role for SOCS3




in the negative regulation of cytokine signals involved in

placental development (Roberts et al., 2001).

SOCS1, SOCS2 and SOCS3 mRNAs have been detectedby RT–PCR in human amnion, choriodecidua and villous

placenta at term regardless of labour status (Blumenstein et al.,

2002). SOCS protein expression was at or below the limit

of detection by immunoblotting in the term amnion and

choriodecidua. In contrast, SOCS1 and SOCS3 were readily

detectable in the villous placenta prior to labour but were

undetectable after labour (Figure 2A), whereas abundance of

the SOCS2 protein in the placenta appeared to increase with

labour. SOCS1 and -3 are present in the syncytium of term

placental villi before onset of labour with evidence of nuclear

localization (Figure 2B); sporadic immunostaining is also

observed in the mesenchyme (Hofbauer cells) and weakly in

the endothelium lining the microcapillaries. No SOCS immu-

nostaining is present in placenta post-labour. The decreasedexpression of SOCS proteins in the placenta may provide a

mechanism by which inflammatory cytokines enter into a

positive feedback loop of inflammatory changes leading to

membrane rupture, cervical ripening, myometrial contraction,

and delivery. Factors responsible for down-regulating placen-

tal SOCS expression are currently being evaluated. To date,

the placenta appears to be excluded from the inflammatory

process of parturition (Keelan et al., 1999b), although contro-

versial reports on changes in placental production of IL-6 and

IL-8 with parturition exist (Shimoya et al., 1992; Keelan et al.,

1999b). The placenta might, therefore, play a more important

Figure 2. Protein expression for SOCS family members in human villous placenta. In panel A, densitometric analysis of Western Blots revealed a significantreduction in placental SOCS1 and SOCS3 protein with spontaneous labour (SL) compared to non-laboured (NL) term samples obtained after Caesarean section(means.d., P<0.05; n=3). SOCS2 protein levels did not change significantly with labour. However, western blots showed a diff erential expression of SOCS2protein with an increase in molecular weight SOCS2 following labour (data derived from M Blumenstein et al., Identification of suppressors of cytokine signalling(SOCS) proteins in human gestational tissues: diff erential regulation is associated with the onset of labour. Journal of Clinical Endocrinology & Metabolism, 87,1094–7, 2002, The Endocrine Society.). Panel B: Immunodetection of SOCS3 in sections of paraffin embedded term villous placenta reveals intense stainingfor SOCS3 positive syncytiotrophoblast (ST) in term placenta without labour compared to weak staining in laboured placenta. Control slides which receivedanti-SOCS3 antibody pre-adsorbed to SOCS3 blocking peptide were devoid of staining. Immunoreactive placental SOCS1 utilizing a corresponding anti-SOCS1antibody (Zymed) showed a similar pattern to SOCS3 with strong staining in the ST in placenta without labour and weak staining in sections from labouredplacenta (data not shown). Magnification, 200. Scale bars, 10 .




part in cytokine signalling in the process of labour than is

currently thought and this process may well be controlled by

SOCS proteins.

CYTOKINE REGULATION OF INTRAUTERINE

PROSTAGLANDIN PRODUCTION

Regulation of arachidonic acid metabolism in the gestational

membranes is believed to be key to the maintenance of

pregnancy and the initiation and progression of labour inwomen. Extensive studies over many decades have charted

changes in prostanoid levels and prostanoid production rates in

intrauterine tissues prior to and during labour (Mitchell et al.,

1995; Olson, Mijovic and Sadowsky, 1995). Biosynthetic

capacity for prostaglandins, especially of amnion-derived

PGE2, increases in women with term or preterm labour (Gibb,

1998). More recent focus has been on the changes in expres-

sion of the two isoforms of PGHS and their respective roles in

the biosynthesis of prostanoids in parturition (Teixeira et al.,

1994; Slater et al., 1995; Mijovic et al., 1998). Similarly, the

upregulation of PGHS-2 expression by cytokines in gestational

tissues has been the subject of intensive investigation (Kniss,

1999). It has become dogma that cytokines regulate prosta-

glandin production and that this is an important aspect of

parturition (Hansen et al., 1999); cytokines such as TNF-

and IL-1 have been shown by numerous studies to act in a

coordinated fashion at multiple points of the prostanoid

biosynthetic pathway (Figure 3). Production of prostaglandins

by cells from the amnion (Romero et al., 1989; Bry and

Hallman, 1992), chorion (Lundin-Schiller and Mitchell, 1991),

decidua (Mitchell, Edwin and Romero, 1990), and myo-

metrium (Hertelendy et al., 1993; Pollard and Mitchell, 1996)is enhanced by IL-1 and TNF-, at least in part through

increased expression of prostaglandin H synthase (PGHS)-2

(Hansen et al., 1999; Kniss, 1999; Rauk and Chiao, 2000). The

stimulatory eff ects of LPS on choriodecidual PG production is

predominantly dependent upon local TNF- release and

action (Sato, Keelan and Mitchell, 2003). IL-6 (albeit at high

doses) has also been shown to stimulate prostaglandin produc-

tion by the amnion and decidua (Mitchell et al., 1991), while

the chemokine macrophage inhibitory protein (MIP)-1

stimulates amnion and chorion cell prostaglandin production

(Dudley, Edwin and Mitchell, 1996). The important

Figure 3. Cytokine-prostaglandin interactions. Proinflammatory cytokines such as TNF- act in a coordinated fashion to up-regulate prostanoid biosynthesis anddown-regulate metabolism. Eff ects on expression and activity of isomerases and PG receptors in gestational tissues are, as yet, unknown. Figure modified andredrawn from Hansen et al. (Key enzymes of prostaglandin biosynthesis and metabolism. Coordinate regulation of expression by cytokines in gestational tissues:a review. Prostaglandins Other Lipid Mediators, 57, 243–57, 1999, with permission from Elsevier Science).




inflammation-associated transcription factor NF-B has been

reported to be constitutively activated in term amnion, poss-

ibly reflecting a functional progesterone withdrawal prior to

labour onset (Allport et al., 2001). Transcriptional activation

by NF-B in amnion epithelial and mesenchymal cells is

induced by IL-1, resulting in increased levels of PGHS-2

protein (Allport et al., 2001; Yan et al., 2002). IL-1 has also

recently been implicated in the mechanism of stretch-inducedtranscriptional activation of PGHS-2 in the amnion and

decidua adjacent to the cervix following labour (Terakawa

et al., 2002).

In addition to regulation at the level of synthesis,

prostaglandin concentrations can also be modulated through

regulation of catabolic inactivation. The enzyme that

catabolizes prostaglandins to inactive metabolites, 15-

hydroxyprostaglandin dehydrogenase (PGDH), is abundant in

the chorion, placental trophoblast, and (to a lesser extent) the

decidua (Cheung et al., 1992; Erwich and Keirse, 1992;

Germain et al., 1994). Its activity is postulated to act as a

metabolic barrier to prevent prostaglandins in the amniotic

fluid from acting upon the myometrium. PGDH expression

and activity in gestational membranes and cultured chorionic

trophoblast is decreased by IL-1 and TNF- (Brown et al.,

1998; Mitchell et al., 2000; Pomini et al., 2000). The eff ect of

TNF- on PGDH mRNA levels is reduced by IL-10 (Pomini,

Caruso and Challis, 1999). PGDH protein and activity in

chorionic trophoblast of the lower uterine segment has been

shown to decrease with term labour, possibly contributing to

the activation of the myometrium (Sangha et al., 1994; Van

Meir et al., 1996).

Prostanoid isomerases synthases

While much attention has focused on the regulation of pros-

taglandin H synthases (PGHS) 1 and 2 with term and preterm

labour, prostanoid biosynthesis is also modulated by the

relative amounts of the various prostanoid isomerases and

synthases expressed within a tissue. These enzymes metabolize

the product of PGHS, PGH2. Unlike PGHS-1 and -2, these

enzymes have, until recently, received little attention in

gestational tissues.

Human prostaglandin D, E-, F- and I-synthases and TXA

synthases (PGDS, PGES, PGFS, PGIS and TXAS, respect-

ively) have all been recently cloned, characterized, and theirco-factor requirements detailed. Two unrelated genes encode

two PGDS enzymes, hematopoietic PGDS (H-PGDS)

(Kanaoka et al., 2000) and -trace/lipocalin-type PGDS

(L-PGDS) (Urade and Hayaishi, 2000). H-PGDS is a

cytosolic protein while L-PGDS is secreted. Similarly, two

PGES enzymes have been identified that are encoded by

two separate genes, a cytosolic (cPGES) (Tanioka et al., 2000)

and membrane bound (mPGES) form ( Jakobsson et al., 1999;

Forsberg et al., 2000; Murakami et al., 2002).

Studies of the regulation of expression of the PG

isomerases/synthases are sparse. Evidence of stimulation of

PGES expression by pro-inflammatory cytokines has been

described (Forsberg et al., 2000). IL-1 has also been reported

to regulate PGIS expression, although both positive (Tanabe

et al., 1995; Ullrich et al., 1997) and negative eff ects (Zou

et al., 1998) have been reported. At a recent meeting, several

groups, including ourselves, presented preliminary data on the

localization and regulation of PG synthases in gestational

tissues (Gibb et al., 2002; Marvin et al., 2002b,c; Meadowset al., 2002a,b; Slater, Astle and Thornton, 2002). It would

appear that, somewhat surprisingly, there are no dramatic

changes in abundance of either form of PGES with term

labour, although there is some evidence of changes in intra-

cellular localization with labour. Clearly, the role of PG

synthases in the processes of pregnancy and parturition will be

an area of intense investigation over the proceeding few years.

PROSTANOID REGULATION OF CYTOKINE

PRODUCTION

Literature relating to the reciprocal actions of prostanoids oncytokine synthesis and release in gestational tissues is also

sparse. PGE2, which is produced within the cervix during

labour in response to leukocytosis, mechanical stressors and

exposure to cytokines, stimulates IL-8 release from cervical

tissue, aff ects proteolytic enzyme activity and induces cervical

ripening (Denison, Calder and Kelly, 1999; Ekman et al.,

1995). Although amnion expresses several forms of EP recep-

tor (Helliwell et al., unpublished data), studies assessing the

eff ects of the primary prostanoids on amnion cytokine produc-

tion identified only thromboxane as a candidate regulator

(Keelan et al., 2000). Thromboxane receptor agonists stimu-

lated production of both IL-6 and IL-8 by amnion-like WISHcells and primary amnion explants. Similar studies in placental

explants have yielded negative findings to date (Higgie,

Mitchell and Keelan, 2000). However, PGE2 has been reported

to stimulate the release of MCP-1, IL-8 and IL-10 by term

placental cotyledons in a perfusion system, suggesting that

some capacity for a cytokine-prostaglandin autoregulatory loop

exists in the placenta (Denison, Calder and Kelly, 1999). The

actions of prostaglandins D2, J2 and their metabolites in

gestational tissues are discussed below.

CYTOKINE—PROSTANOID ACTION AND

INTERACTIONS DURING PARTURITION

Membrane remodelling and rupture

Digestion of extracellular matrix of the foetal membranes

occurs at term and is carried out largely by locally produced

matrix metalloproteinases (MMPs), the activity of which is

negatively regulated by tissue inhibitors of matrix metallopro-

teinases (TIMPs). Changes in activity of plasminogen acti-

vator, MMPs and TIMPs in amniotic fluid and gestational

tissues are associated with the onset of labour and rupture of

the foetal membranes (Bryant-Greenwood and Yamamoto,




1995; Vadillo-Ortega et al., 1996; Athayde et al., 1998; Riley

et al., 1999). Cytokines may be among the factors responsible

for the increased levels of MMP expression and activity in the

membranes associated with rupture. Intrauterine infection

has been associated with higher MMP-9 concentrations in

amniotic fluid, whether or not membrane rupture occurred

(Draper et al., 1995; Athayde et al., 1998). This increase in

MMP-9 may reflect an increase in leukocyte colonization of the amniotic fluid. TNF-, IL-1, IL-6 and M-CSF have all

been shown to increase MMP gelatinase secretion by first

trimester trophoblast, while TGF- decreases this activity

(Meisser et al., 1999). TNF- stimulates production of MMPs

(-1 and -3) and plasminogen activator by chorion and decreases

the production of TIMP (So, 1993), while IL-1 increases

synthesis of MMP-1 by cultured chorionic cells (Katsura et al.,

1989). Treatment of amniochorion explants with lipopolysac-

charide (LPS), a stimulator of cytokine release, also results in

an increase in synthesis and release of MMP-2 and a decrease

in the synthesis and release of its tissue inhibitor (Fortunato,

Menon and Lombardi, 2000). The stimulatory eff ect of LPS

on MMP-2 and -9 release in the foetal membranes is inhibited

by IL-10 (Fortunato et al., 2001). In a recent study in a

primate model of intrauterine infection, intra-amniotic IL-1

administration was reported to increase levels of latent MMP-9

in amniotic fluid as a result of increased MMP-9 expression in

amnion and chorion (Vadillo-Ortega et al., 2002). PGF2 has

recently been shown to act on the decidua to increase produc-

tion of MMP-2 and -9 in the decidua (but not amnion or

chorion), thereby increasing gelatinolytic activity (Ulug et al.,

2001).

Concentrations of IL-8 have been significantly correlated

with those of MMP-9 in the amnion and chorion during the

later stages of cervical dilation (Osmers et al., 1995b). IL-8production in chorion and amnion is stimulated by IL-1 and

TNF- (Trautman et al., 1992; Keelan, Sato and Mitchell,

1997). Interestingly, both IL-8 production and collagenase

activity in the foetal membranes are increased by mechanical

stretching (Maehara et al., 1996; Maradny et al., 1996),

pointing to an indirect mechanism of action for these cytokines

in extracellular matrix remodelling. There is some evidence

that apoptosis also contributes to weakening of the foetal

membranes prior to rupture, particularly in the chorion layer

at the site of rupture (Runic et al., 1998; McLaren, Taylor and

Bell, 1999). Expression of the proapoptotic genes bax and p53

is increased in amniochorion from pregnancies complicated bypremature rupture of the membranes, while expression of the

antiapoptotic gene bcl-2 is decreased (Fortunato et al., 2000).

Apoptotic cell death may be a reaction to the destruction of

extracellular matrix in the membranes or a significant and

separate part of membrane thinning and rupture. TNF-, in

concert with IFN, induces trophoblast apoptosis (Yui et al.,

1994; Garcia-Lloret et al., 1996). TNF- and other family

members may thus be involved in the normal rupture of foetal

membranes at term, through induction of apoptosis. A role for

PGE2 in inducing necrosis in amnion epithelial cells has

recently been proposed (Surendran, 2001).

Cervical ripening

Cervical ripening, remodelling and softening of the cervix, is a

requirement for the normal onset and progress of labour. The

processes of cervical ripening are similar to those involved in

induction of membrane rupture, including changes in extra-

cellular matrix composition, invasion of neutrophils, and tissue

remodelling by proteolytic enzymes (Liggins, 1981; Osmerset al., 1995a; Winkler and Rath, 1999). Cytokines, particularly

IL-8, have been implicated in the process of cervical ripening.

IL-8 synthesis and secretion is greatly increased in term versus

nonpregnant cervix and concentrations of IL-8 in the cervix

and lower uterine segment increase with cervical ripening

(Sennstrom et al., 1997, 1998; Winkler et al., 1998). The

increase in IL-8 during cervical ripening correlates with

increases in leukocyte infiltration and concentrations of MMPs

in the tissue (Osmers et al., 1995a,b; Winkler et al., 1999a,b).

Concentrations of IL-1, TNF- and IL-6 in the lower

uterine segment also increase with cervical dilation (Winkler et

al., 1998) and have been shown to aff ect production of TIMPs

and MMPs by human cervical fibroblasts and smooth musclecells (Ito, Leppert and Mori, 1990; Ito et al., 1990; Sato, Ito

and Mori, 1990). Increases in IL-6, G-CSF and MCP-1,

cytokines which aff ect proliferation and activation of immune

cells, also occur with cervical ripening (Denison et al., 2000).

While the majority of cytokine eff ects on cervical ripening

are likely to be induced by locally produced cytokines, it is

possible that cytokines secreted by the placenta and mem-

branes may have indirect eff ects. IL-1 has been shown to

induce IL-8 secretion by human cervical fibroblasts in vitro,

alone and in concert with TGF-1 and growth factors

(Winkler et al., 1998; Winkler et al., 2000). PGE2, secretion of

which is influenced by many cytokines, also stimulates IL-8release from cervical tissue, aff ects proteolytic enzyme activity,

and induces cervical ripening (Ekman et al., 1995; Denison,

Calder and Kelly, 1999).

PGD2 and its derivatives

Although the placenta produces considerable amounts of the

anti-inflammatory PGD2 (Mitchell, Kraemer and Strickland,

1982), the potential roles for anti-inflammatory PGs in main-

tenance of pregnancy and control of labour have only recently

begun to be explored. PGD2 suppresses pro-inflammatorycytokine production, and in the placenta inhibits IL-6 and

IL-8 production (Higgie, Mitchell and Keelan, 2000). PGD2

also spontaneously isomerizes to PGJ2 and to further

derivatives such as 15-deoxy-12,14 PGJ2 (Fukushima, 1990;

Fukushima, 1992); PGJ2 and its derivatives are ligands for

peroxisome proliferator activated receptors (PPARs) (Forman

et al., 1995), members of the steroid receptor superfamily that

are extensively expressed in gestational tissues (Marvin et al.,

2000). These transcription factors, particularly PPAR-,

inhibit pro-inflammatory cytokine production ( Jiang, Ting and

Seed, 1998; Ricote et al., 1998) and modulate fatty acid,




prostaglandin, and steroid hormone metabolism in other sys-

tems (Gulick et al., 1994; Rodriguez et al., 1994). In addition,

15-deoxy-12,14 PGJ2 inhibits activation of NF-B/Rel

(Straus et al., 2000) and has been shown to inhibit TNF-

stimulated PGHS-2 expression in cultured trophoblasts

(Kniss, 1999). Lapas et al. (2002) recently reported that

15-deoxy-12,14 PGJ2 at high concentrations inhibits cytokine

production by LPS-stimulated amnion, choriodecidual andplacental cells in vitro, possibly via inhibition of NF-B

activity. These data support an earlier report showing similar

eff ects in cultured primary trophoblasts, although a reduction

in cell viability was observed at high concentrations of

15-deoxy-12,14-PGJ2 (Keelan, Anand and Mitchell, 2001).

This PG metabolite has been shown to induce apoptosis in

JEG-3 choriocarcinoma cells (Keelan et al., 1999d) and WISH

amnion-like epithelial cells (Keelan et al., 2001), although its

eff ects on viability of primary (non-transformed) cells have yet

to be fully investigated. Hence PGD2 and its derivatives may

be involved in the remodelling of gestational tissues, resolution

of inflammation, and prevention of preterm labour.

SUMMARY

In the context of parturition the focus of prostaglandin

research in the late 20th century was the interaction between

cytokines and PGHS-2 expression with term and preterm

labour. More recent studies are extending this interest to

include the expression of isomerases/synthases that determine

the profile of prostanoids produced within a given tissue.

Novel targets and actions of the D-series prostaglandins are

also being actively investigated; their synthesis within ges-

tational tissues alludes to some important functions, including

autocrine/paracrine eff ects within the foetal membranes. Simi-larly, it is now clear that a large array of cytokines and

chemokines are expressed in these tissues, some of which

appear to play roles in both term and preterm labour. The

increased expression of chemokines observed in association

with infection-driven preterm labour highlights their impor-

tance in the pathophysiology of this syndrome, although it

remains to be seen which of the many members of this group

are key to the process. The factors responsible for triggering

chemokine expression in the gestational membranes in non-

infection-related preterm labour also awaits elucidation.

Finally, cytokine receptor expression and signalling is now

being investigated in these tissues to identify labour-associatedchanges that may give further insight into the role of various

cytokines in the normal parturition process. Although some

interesting preliminary findings have been presented, this is an

area in which there is plenty of scope to uncover new and novel

insights into cytokine-prostaglandin interactions in pregnancy

and labour.

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