review cytokines and neuro–immune–endocrine interactions...

Review

Cytokines and neuro–immune–endocrine interactions:

a role for the hypothalamic–pituitary–adrenal revolving axis

John J. Haddada,*, Nayef E. Saadeb, Bared Safieh-Garabedianc

aSeveringhaus-Radiometer Research Laboratories, Molecular Neuroscience Research Division, Department of Anesthesia and Perioperative Care,

University of California at San Francisco, School of Medicine, Medical Sciences Building S-261, 513 Parnassus Avenue,

San Francisco, CA 94143-0542, USAbDivision of Molecular and Behavioral Neuroscience Research, Departments of Human Morphology and Physiology, Faculty of Medicine,

American University of Beirut, Beirut 11-0236, LebanoncDepartment of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut 11-0236, Lebanon

Received 24 July 2002; received in revised form 20 September 2002; accepted 23 September 2002

Abstract

Cytokines, peptide hormones and neurotransmitters, as well as their receptors/ligands, are endogenous to the brain, endocrine and immune

systems. These shared ligands and receptors are used as a common chemical language for communication within and between the immune

and neuroendocrine systems. Such communication suggests an immunoregulatory role for the brain and a sensory function for the immune

system. Interplay between the immune, nervous and endocrine systems is most commonly associated with the pronounced effects of stress on

immunity. The hypothalamic–pituitary–adrenal (HPA) axis is the key player in stress responses; it is well established that both external and

internal stressors activate the HPA axis. Cytokines are chemical messengers that stimulate the HPA axis when the body is under stress or

experiencing an infection. This review discusses current knowledge of cytokine signaling pathways in neuro– immune–endocrine

interactions as viewed through the triplet HPA axis. In addition, we elaborate on HPA/cytokine interactions in oxidative stress within the

context of nuclear factor-nB transcriptional regulation and the role of oxidative markers and related gaseous transmitters.

D 2002 Elsevier Science B.V. All rights reserved.

Keywords: Brain; CNS; Cytokine; HPA; Inflammation; Neuroimmunology; Neuropeptide; Neurotransmitters; Oxidative stress; Transcription

0165-5728/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.

PII: S0165 -5728 (02 )00357 -0

Abbreviations: ADX, adrenalectomy; ACTH, adrenocorticotropic hormone; CO, carbon monoxide; CNS, central nervous system; CORT, corticosterone;

CRF, corticotropin-releasing factor; CRH, corticotropin-releasing hormone; CRH-R1, CRH-receptor type 1; COX, cyclooxygenase; Dex, dexamethasone;

DPH, diphenhydramine; ET, endothelin; EtOH, ethanol; NE, norepinephrine; GR, glucocorticoid receptor; GH, growth hormone; HN, heteronuclear; HA,

histamine; H2O2, hydrogen peroxide; HPA, hypothalamic–pituitary–adrenal; HPG, hypothalamic–pituitary–gonadal; HPT, hypothalamic–pituitary– thyroid;

Indo, indomethacin; InB, inhibitory-nB; IFN, interferon; IL, interleukin; IL-1ra, IL-1 receptor antagonist; LPS, lipopolysaccharide-endotoxin; LH, luteinizing

hormone; PVN, medial parvocellular paraventricular/hypothalamic paraventricular nucleus; ME, median eminence; a-MSH, a-melanocyte-releasing hormone;

MEP, mepyramine; mRNA, messenger ribonucleic acid; MET, metiamide; MHPG, 3-methoxy-4-hydroxyphenylethyleneglycol; MR, mineralocorticoid

receptor; SIN-1, 3-morpholino-sydnonimine; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase; NDGA,

nordihydroguaiaretic acid; NRS, normal rabbit serum; NF-nB, nuclear factor-nB; NTS, nucleus tractus solitarius; L-NAME, NN-nitro-L-arginine-methylester;

OT, oxytocin; PF, pair-fed; PBMNC, peripheral blood mononuclear cells; PRL, prolactin; PMZ, promethazine; PKA, protein kinase A; RA, rheumatoid

arthritis; TRX, thioredoxin; TSH, thyroid-stimulating hormone; TGF, transforming growth factor; TNF, tumor necrosis factor; VP, vasopressin; VLM,

ventrolateral medulla.

* Corresponding author. Tel.: +1-415-476-8984; fax: +1-415-476-8841.

E-mail address: [email protected] (J.J. Haddad).

www.elsevier.com/locate/jneuroim

Journal of Neuroimmunology 133 (2002) 1–19

1. Introduction

Cytokines are mediators of inter- and intracellular com-

munications (Rouveix, 1997; Saade et al., 1997; Safieh-

Garabedian et al., 1997a,b; Boraschi et al., 1998; Dinarello,

2000; Haddad, 2000; Oppenheim, 2001; Holloway et al.,

2002). These peptides contribute to a chemical signaling

language that regulates development, tissue repair, haemo-

poiesis, inflammation and the specific and nonspecific

immune responses (Safieh-Garabedian et al., 1997b, 1999,

2002a,b; Holloway et al., 2002). Potent cytokine polypep-

tides (such as interleukin (IL)-1, IL-6, IL-8 and tumor

necrosis factor (TNF)-a) have pleiotropic activities and

functional redundancy; in fact, they act in a complex,

intermingled network where one cytokine can influence

the production of, and response to, many other cytokines.

It is also now clear that the pathophysiology of inflamma-

tory hyperalgesia, infection and autoimmune and malignant

diseases can be explained, at least in part, by the induction

of cytokines and the subsequent protracted cellular res-

ponses (Kanaan et al., 1997; Saade et al., 1998, 1999;

Haddad and Fahlman, 2002; Holloway et al., 2002). Of

note, cytokines and cytokine antagonists have also exhibited

therapeutic potential in a number of chronic and acute

diseases (Kanaan et al., 1996; Dinarello, 2000; Haddad et

al., 2000; Oppenheim, 2001; Holloway et al., 2002). The

mechanisms, from both the neural and immunological

perspective, involved in stress-induced alteration of immune

function are being studied (Safieh-Garabedian et al., 1996,

1997a, 2002a,b; Haddad and Land, 2000a,b; Haddad, 2002).

The immune system is regulated in part by the central

nervous system (CNS), acting principally via the hypothala-

mic–pituitary adrenal (HPA) axis and the sympathetic

nervous system (SNS) (Safieh-Garabedian et al., 2002a,b).

In recent years, our understanding of the interactions

between the HPA axis and immune-mediated inflammatory

reactions has expanded enormously. This review outlines

the influences that the HPA axis and immune-mediated

inflammatory reactions exert on each other and discusses

the mechanisms whereby these interactions are mediated.

Furthermore, we discuss HPA interactions and oxidative

stress evolution within the context of a potential role for the

transcription factor NF-nB, which regulates a plethora of

cellular functions including proinflammatory-mediated pro-

cesses, and the role of gaseous transmitters.

2. Cytokines in the CNS: neuro–immune–endocrine

interactions

The neuroendocrine and immune systems communicate

bidirectionally (Fig. 1). The neuro–immune–endocrine in-

terface is mediated by cytokines, such as IL-1 and TNF-a,

acting as auto/paracrine or endocrine factors regulating

pituitary development, cell proliferation, hormone secretion,

and feedback control of the HPA axis (Hall et al., 1985;

Woiciechowsky et al., 1999; Safieh-Garabedian et al.,

2002a,b). Increasing evidence supports the hypothesis that

there are bidirectional circuits between the CNS and the

immune system. Soluble products that appear to transmit

information from the immune compartment to the CNS

include thymosins, lymphokines and certain complement

proteins. Opioid peptides, adrenocorticotropic hormone

(ACTH) and thyroid-stimulating hormone (TSH) are addi-

tional products of lymphocytes that may function in immu-

nomodulatory neuroendocrine circuits. It was proposed that

the term ‘immuno-transmitter’ be used to describe molecules

that are produced predominantly by cells that comprise the

immune system but that transmit specific signals and infor-

mation to neurons and other cell types (Hall et al., 1985;

Safieh-Garabedian et al., 1997a, 2002a,b; Turnbull and

Rivier, 1999; Woiciechowsky et al., 1999; Haddad et al.,

2000; Haddad and Land, 2002a,b).

Several cytokines are known to affect the release of

anterior pituitary hormones by an action on the hypothal-

amus and/or the pituitary gland. The major cytokines

involved are IL-1, IL-2, IL-6, TNF-a and interferon (IFN)

(Bumiller et al., 1999). The predominant effects of these

cytokines are to stimulate the HPA axis and to suppress the

hypothalamic–pituitary–thyroid (HPT) and gonadal axes,

Fig. 1. Scheme for molecular communications circuits existing between the

immune and neuroendocrine systems and involving shared ligands and

receptors.

J.J. Haddad et al. / Journal of Neuroimmunology 133 (2002) 1–192

and growth hormone (GH) release. However, the relative

importance of systemically and locally produced cytokines

in achieving these responses and their precise sites of action

have not been fully established (Safieh-Garabedian et al.,

1997b, 2002a,b; Haddad et al., 2001a,b,c). There is cumu-

lating evidence that there are significant interactions

between the immune and neuroendocrine systems which

may explain, at least in part, some of the effects on growth,

thyroid, adrenal and reproductive functions which occur in

acute and chronic disease (Fig. 2) (Jones and Kennedy,

1993). During stimulation of the immune system (e.g.

during infectious diseases), peculiar alterations in hormone

secretion occur (hypercortisolism, hyperreninemic hypoal-

dosteronism, euthyroid sick syndrome, hypogonadism). The

role of cytokines in these alterations is being elucidated and

established (Hermus and Sweep, 1990; Cunningham and De

Souza, 1993; Stenzel-Poore et al., 1993; Barna et al., 1995;

Saade et al., 1997; Bumiller et al., 1999; Haddad et al.,

2002a,b,c; Safieh-Garabedian et al., 2002a,b).

2.1. IL-1/IL-6/TNF-a and HPA responses

The bilateral communication between the immune and

neuroendocrine systems plays an essential role in modulat-

ing the adequate response of the HPA axis to the stimulatory

influence of ILs and stress-related mediators (Fig. 2) (Span-

gelo et al., 1995). It is thus reasonable to assume that

inappropriate responses of the HPA axis to ILs might play

a role in modulating the onset of pathological conditions

such as infections and related pathologies (Rivier, 1994).

Ever since two distinct molecules of IL-1 (IL-1a and IL-1h)were cloned, sequenced and expressed, it has been a matter

of investigation whether these two forms of IL-1 possess an

identical spectrum of biological activities (Anforth et al.,

1998). In situ histochemical techniques were used to inves-

tigate the distribution of cells expressing type I IL-1 receptor

messenger ribonucleic acid (mRNA) in the CNS, pituitary

and adrenal gland of the mouse. For instance, hybridization

of 35S-labeled antisense cRNA probes derived from a

murine T-cell IL-1 receptor cDNA revealed a distinct

regional distribution of the type I IL-1 receptor, both in

brain and in the pituitary gland (Cunningham et al., 1992;

Quan et al., 1998). In the brain, an intense signal was

observed over the granule cell layer of the dentate gyrus,

over the entire midline raphe system, over the choroid

plexus and over endothelial cells of postcapillary venules

throughout the neuraxis. A weak to moderate signal was

observed over the pyramidal cell layer of the hilus and CA3

region of the hippocampus, over the anterodorsal thalamic

nucleus, over Purkinje cells of the cerebellar cortex and in

scattered clusters over the external-most layer of the median

eminence. In the pituitary gland, a dense and homogene-

ously distributed signal was observed over the entire ante-

rior lobe. Furthermore, no autoradiographic signal above

background was observed over the posterior and intermedi-

ate lobes of the pituitary, or over the adrenal gland, provid-

ing evidence for discrete receptor substrates subserving the

central effects of IL-1, thus supporting the notion that IL-1

acts as a neurotransmitter/neuromodulator in brain. It also

supports the fact that IL-1-mediated activation of the HPA

axis occurs primarily at the level of the brain and/or pituitary

gland (Elenkov et al., 2000).

IL-1 and other related proinflammatory cytokines are

potent activators of the HPA axis (Rivier, 1994; Barna et al.,

1995; Rivest, 1995; Xu et al., 1999; Liege et al., 2000;

Chesnokova and Melmed, 2002). Current studies of IL-1

and its involvement in the HPA axis have indicated that

there is a clear-cut differential response to IL-1a and IL-1h.For example, the intravenous injection of human recombi-

nant IL-1h in conscious, freely moving rats significantly

increased the plasma levels of ACTH in a dose-related

manner, whereas IL-1a did not, suggesting that the two

members of the IL-1 family may have a different spectrum

of biological actions (Uehara et al., 1987a). Furthermore,

additional investigations clarified the mechanism by which

IL-1 activates the HPA axis. For example, the ACTHFig. 2. Classic components of the CNS systems.

J.J. Haddad et al. / Journal of Neuroimmunology 133 (2002) 1–19 3

response to IL-1 was completely abolished by pre-injection

of rabbit antiserum generated against rat corticotropin

releasing factor (CRF) but not by normal rabbit serum

(NRS) (Uehara et al., 1987b; Payne et al., 1994). The IL-

1-induced ACTH release did not seem to be caused by a

general stress effect of IL-1 because plasma PRL levels,

another indicator of a stress response, were not altered by

IL-1 injection, suggesting that IL-1 acts centrally in the

brain to stimulate the secretion of CRF, thereby eliciting

ACTH release, and that a direct action of IL-1 on the

pituitary gland is unlikely. In addition, it has reported that

intraperitoneal injection of recombinant IL-1 into mice

increased the cerebral concentration of the norepinephrine

(NE) catabolite, 3-methoxy-4-hydroxyphenylethyleneglycol

(MHPG), probably reflecting increased activity of noradre-

nergic neurons (Dunn, 1988). This effect was dose-depend-

ent and was largest in the hypothalamus, especially the

medial division. Of note, tryptophan concentrations were

also increased throughout the brain and the increase of

MHPG after IL-1 administration paralleled the increase of

plasma corticosterone. In contrast to prior observations

(Uehara et al., 1987a), both the a- and h-forms of IL-1

were effective, but the activity was lost after heat treatment

of the IL-1 (Dunn, 1988).

Noradrenergic neurons with terminals in the hypothala-

mus are known to regulate the secretion of CRF, thus

suggesting that IL-1 activates the HPA axis by activating

these neurons. Because the initiation of an immune response

is known to cause systemic release of IL-1, this cytokine

may be an immuno-transmitter communicating the immu-

nologic activation to the brain. The IL-1-induced changes in

hypothalamic MHPG may explain the increases of electro-

physiological activity, the changes of hypothalamic NE

metabolism and the increases in circulating glucocorticoids

reported to be associated with immunologic activation and

frequently observed in infected animals (Dunn, 1988). In

support of these observations, ACTH secretion by the

anterior pituitary is shown to be stimulated by catechol-

amines in vivo and in vitro (Boyle et al., 1988). The nature

of the response in vivo is controversial but appears to be

mediated by h-adrenergic receptors, whereas the response isdependent on a-adrenergic receptors in cultured anterior

pituitary cells. By using a superfusion technique, Boyle et al.

(1988) demonstrated that catecholamine stimulation of

ACTH release from rat anterior pituitaries changed with

time from a predominantly h-adrenergic-mediated event to a

predominantly a-adrenergic-mediated event. For instance,

the release of ACTH from anterior pituitary glands was

stimulated by the h-adrenergic agonist, isoproterenol (Boyleet al., 1988). However, the ACTH secretory response to the

a-adrenergic agonist phenylephrine is less than that of

isoproterenol during the same time period. Furthermore,

the responsiveness to the h-adrenergic agonist declined

and the response to the a-adrenergic agonist increased,

marking that catecholamine-inducible ACTH release could

be mediated by an a-adrenergic pathway. Of note, the

addition of IL-1 alone to the medium from the beginning

of the superfusion did not modify basal ACTH secretion

rates and did not affect the acquisition of the response to

phenylephrine. However, the presence of IL-1 did allow the

maintenance of the full ACTH secretory response to iso-

proterenol; this effect was reversed by an IL-1 antagonist

(Boyle et al., 1988), suggesting an additional way in which

immune regulators might interact with the HPA axis

(Gwosdow et al., 1990; Hermus and Sweep, 1990; Kapcala

et al., 1995).

In concert, it has been reported that intracerebroventric-

ular injections of IL-1 can cause the release of ACTH. For

instance, IL-1h produced an immediate increase in plasma

corticosterone and ACTH (Brown et al., 1991). Using a

potent steroidogenic dose of IL-1h (c 5 ng), intracerebro-

ventricular injection resulted in the suppression of splenic

macrophage IL-1 secretion following stimulation by lip-

opolysaccharide-endotoxin (LPS) in vitro. Macrophage

transforming growth factor (TGF)-h secretion, however,

was not affected, indicating a differential action of IL-1hon macrophage cytokine production (Brown et al., 1991).

Following adrenalectomy (ADX), the suppressive effect of

IL-1h was reversed and resulted in the stimulation of

macrophage IL-1 secretion, indicating that the suppression

was mediated by adrenocorticol activation. However, surgi-

cal interruption of the splenic nerve to eliminate autonomic

innervation of the spleen also prevented the macrophage

suppressive signal. Furthermore, the combination of ADX

and splenic nerve section resulted in a potent stimulatory

effect of intracerebroventricular IL-1h on splenic macro-

phage IL-1 secretion that was greater than either ADX or

splenic nerve section alone (Brown et al., 1991). These

results supported the concept of a negative feedback on

macrophage IL-1 secretion by the central action of IL-1hand indicated that both the HPA axis and the sympathetic

nervous system mediate this effect.

Further conflicting reports, however, have been published

with regards to a crucial role of catecholamines in IL-1-

mediated regulation of the HPA axis. The hypothalamus

seems to be an important site of action of IL-1 on the HPA

axis, thereby inducing CRF secretion (catecholamines are

important modulators of CRF secretion); in turn, IL-1

stimulates catecholamine release from the hypothalamus.

In this respect, the possible involvement of hypothalamic

catecholamines in the effect of IL-1h on hypothalamic CRF

secretion, by using an in vitro rat hypothalamic continuous

perifusion system was investigated. For instance, neither in

vivo pretreatment with an inhibitor of catecholamine syn-

thesis nor in vitro exposure to a- or h-adrenoceptor antag-onists (phenoxybenzamine or propranolol, respectively), nor

combination of both treatments altered the effect of IL-1 on

CRF secretion from superfused hypothalami, indicating that

catecholamines are not involved in the in vitro stimulatory

action of IL-1 on hypothalamic CRF secretion (Cambronero

et al., 1992a,b). In contrast, IL-1-induced corticosterone

release was shown to occur by an adrenergic mechanism


from rat adrenal gland (Gwosdow et al., 1992). An interest

mechanism was recently reported for IL-1-mediated regu-

lation of the HPA axis. A primary route of peripheral

cytokine signaling was proposed through the stimulation of

peripheral vagal afferents rather than or in addition to direct

cytokine access to brain. Subdiaphragmatic, but not hepatic

vagotomy, blocked IL-1h-induced hypothalamic norepi-

nephrine depletion and attenuated IL-1h-induced increases

in serum corticosterone, suggesting that IL-1 activates the

HPA axis via the stimulation of peripheral vagal afferents

and further support the hypothesis that peripheral cytokine

signaling to the CNS is mediated primarily by stimulation of

peripheral afferents (Fleshner et al., 1995; Propes and

Johnson, 1997; Saade et al., 1998, 1999). Another major

mechanism reported for the action of IL-1 on the HPA axis

involved the amygdala. For example, bilateral ibotenic acid

lesions of the central amygdala substantially reduced ACTH

release and hypothalamic corticotropin-releasing factor and

oxytocin cell c-fos expression responses to IL-1 and IL-8,

suggesting a facilitatory role for this structure in the gen-

eration of HPA axis responses to an immune challenge (Xu et

al., 1999). Since only a small number of central amygdala

cells project directly to the paraventricular nucleus, the

authors then examined the effect of central amygdala lesions

on the activity of other brain nuclei that might act as relay

sites in the control of the HPA axis function. It was found that

bilateral central amygdala lesions significantly reduced IL-

1h-induced c-fos expression in cells of the ventromedial and

ventrolateral subdivisions of the bed nucleus of the stria

terminalis and brainstem catecholamine cell groups of the

nucleus tractus solitarius (A2 noradrenergic cells) and ven-

trolateral medulla (A1 noradrenergic and C1 adrenergic

cells). These findings, in conjunction with previous evidence

of bed nucleus of the stria terminalis and catecholamine cell

group involvement in HPA axis regulation, indicated that

ventromedial and ventrolateral bed nucleus of the stria

terminalis cells and medullary catecholamine cells might

mediate the influence of the central amygdala on the HPA

axis responses to an immune challenge. Thus, these related

data established that the central amygdala influences HPA

axis responses to a systemic immune challenge but indicate

that it primarily acts by modulating the activity of other

control mechanisms. Similarly, an interesting mechanism

implicated the vagus nerve (Hosoi et al., 2000). For instance,

direct electrical stimulation of the central end of the vagus

nerve induced increases in the expression of mRNA and

protein levels of IL-1h in the hypothalamus and the hippo-

campus. Furthermore, expression of CRF mRNA was

increased in the hypothalamus after vagal stimulation (Hosoi

et al., 2000). Plasma levels of ACTH and corticosterone

(CORT), in addition, were also increased by this stimulation,

indicating that the activation of the afferent vagus nerves can

induce production of cytokines in the brain and activate the

HPA axis. Therefore, the afferent vagus nerve may play an

important role in transmitting peripheral signals to the brain

in the infection and inflammation. In concert, dorsal and

ventral medullary catecholamine cell groups were reported

to contribute differentially to systemic IL-1h-induced HPA

axis responses. Medial parvocellular paraventricular cortico-

tropin-releasing hormone (mPVN/CRH) cells are critical in

generating HPA axis responses to systemic IL-1h (Buller et

al., 2001). However, although it is understood that catechol-

amine inputs are important in initiating mPVN CRH cell

responses to IL-1h, the contributions of distinct brainstem

catecholamine cell groups are not known. The authors

examined the role of nucleus tractus solitarius (NTS) and

ventrolateral medulla (VLM) catecholamine cells in the

activation of mPVN CRH, hypothalamic oxytocin (OT)

and central amygdala cells in response to IL-1h. It was

confirmed that PVN 6-hydroxydopamine lesions, which

selectively depleted catecholaminergic terminals, reduced

IL-1h-induced mPVN CRH cell activation (Buller et al.,

2001). The contribution of VLM (A1/C1 cells) versus NTS

(A2 cells) catecholamine cells to mPVN CRH cell responses

was then examined by placing ibotenic acid lesions in either

the VLM or NTS. The precise positioning of these lesions

was guided by prior retrograde tracing studies in which the

location of IL-1h-activated VLM and NTS cells that project

to the mPVN was mapped. Both VLM and NTS lesions

reduced the mPVN CRH and OT cell responses to IL-1h.Unlike VLM lesions, NTS lesions also suppressed the re-

cruitment of central amygdala neurons (Buller et al., 2001).

These studies provided evidence that both the NTS and VLM

catecholamine cells have important, but differential, contri-

butions to the generation of IL-1h-induced HPA axis

responses (Fig. 3).

The in vivo release of ACTH by IL-1 is reportedly

blocked by acute treatment with indomethacin (Indo), a

nonsteroidal anti-inflammatory drug (NSAID), suggesting

an involvement of endogenous prostaglandins in the effect

of cytokines on the HPA axis (Rivier and Vale, 1991;

Betancur et al., 1995; Swain et al., 1995; Bugajski, 1996;

Buller et al., 1998). However, Indo also increases plasma

corticosterone levels, raising the possibility that inhibition of

ACTH release is due to suppressive effects of hypercorti-

colemia rather than to blockade of the stimulatory effects of

IL-1a. It was observed that the intraventricular administra-

tion of Indo completely abolished the rise in plasma ACTH

levels caused by the peripheral injection of this lymphokine

to intact rats (Rivier and Vale, 1991). In contrast, implanta-

tion of intact rats with Indo pellets only partially interfered

with IL-1-induced ACTH secretion. To determine whether

the effect of Indo was due to corticosteroid feedback or

represented a modulating action of prostaglandins them-

selves, a similar series of experiments were carried out in

ADX rats (Rivier and Vale, 1991). In the absence of

corticoid replacement therapy, acute treatment with Indo

did not measurably interfere with the stimulatory effect of

IL-1a. In contrast, Indo blunted, but did not abolish, the

effect of IL-1a in ADX rats pretreated with CORT or

dexamethasone (Dex) to normalize basal ACTH levels.

Thus, the acute ability of Indo to totally block IL-1-induced


ACTH secretion by intact rats appears to be primarily

mediated through corticosteroid feedback. However, results

obtained when a similar experiment was carried out in

adrenalectomized/corticosteroid-treated rats suggested that

the ability of IL-1a to activate the HPA axis might be

partially dependent on the release of prostaglandins. In

concert, the effects of various cyclo- and lipoxygenase

inhibitors on the neurochemical and HPA responses to IL-

1 indicated a role for prostaglandins in IL-1-mediated

activation of the HPA axis. For example, pretreatment of

mice with the cyclooxygenase (COX) inhibitors, Indo or

ibuprofen, failed to prevent the elevations of plasma CORT,

or hypothalamic MHPG or tryptophan that followed intra-

peritoneally administered IL-1 (Dunn and Chuluyan, 1992).

Similar results were obtained with the nonspecific oxygen-

ase inhibitor, BW-755C, and the lipoxygenase inhibitor,

BW-A4C. However, the COX inhibitor, diclofenac, did

attenuate the IL-1-induced elevation of plasma CORT and

the neurochemical changes (Dunn and Chuluyan, 1992). To

resolve the conflicting data on the effect of Indo on the IL-1-

induced elevation of plasma concentration, the effects of

this blocker the response to IL-1 injected intravenously were

recorded (Parsadaniantz et al., 2000). By contrast with the

response to intraperitoneally injected IL-1, that to intra-

venous IL-1 was attenuated by Indo (Dunn and Chuluyan,

1992). Time course of the HPA response to IL-1 was more

rapid following intraperitoneal than intravenous injections;

therefore, the effects of intravenous IL-1, earlier than that to

intraperitoneal IL-1 were subsequently investigated. Forty

minutes following intraperitoneal IL-1, the CORT response

to IL-1 was markedly attenuated, indicating that more than

one mechanism could be involved in the HPA response to

IL-1: the more rapid one, predominant in the case of

intravenous injections, seems to be sensitive to COX inhib-

itors, whereas the slower one is not (Dunn and Chuluyan,

1992). In concert with the aforementioned observations,

glucocorticoids, known to modulate CRF release by a

negative feedback inhibition, have been postulated to exert

a permissive action on the IL-1 effect on CRF secretion

(Cambronero et al., 1992b). Using a continuous perifusion

system of rat hypothalami, results indicated that IL-1h could

exert a more potent effect than IL-1a in stimulating CRF

secretion. The increase in hypothalamic CRF release

induced by IL-1 was rapidly inhibited by both Dex and

CORT (Cambronero et al., 1992b; Betancur et al., 1995).

However, ADX did not modify CRF secretion induced by

IL-1 from the in vitro perifused hypothalami, thus indicating

that IL-1 does not seem to induce CRF secretion by

interfering with an impeding action of glucocorticoids,

although the cytokine effect is negatively modulated by

corticosteroids.

In support of the aforementioned observations, Betancur

et al. (1994) reported that IL-1 and glucocorticoid hormones

represent two key mediators involved in the modulation of

the neuro–immuno–endocrine response to stress. In the

immune system, glucocorticoids modulate IL-1 production

and a number of IL-1 receptors. To this end, a series of

studies investigated the effects of various manipulations of

the HPA axis on IL-1 binding to the murine hippocampus.

Results showed that IL-1 receptor levels in the hippocampus

were slightly decreased below control values in Dex-treated

animals either in subchronic or chronic treatments (Betancur

Fig. 3. The HPA doctrine. (A) Classic components of the HPA–CNS–

immune systems. (B) Neurons of the hypothalamus that synthesize CRF

and vasopressin are found in an area called the paraventricular nucleus

(PVN). These cell bodies send axons to the median eminence; here,

peptides are released from the nerve terminals and are transported through

vessels of the portal system. When they reach the anterior pituitary, these

peptides act on their respective receptors, thereby stimulating ACTH

secretion. (C) Following its release into the general circulation, ACTH acts

on the cortex of the adrenal glands, which manufacture and secrete

glucocorticoids (corticosterone in rodents and cortisol in humans). These

glucocorticoids exert a classical negative feedback influence on the

pituitary, where they inhibit the effect of CRF and VP, and on the PVN,

where they inhibit the synthesis of CRF. Thus, after a stimulus stimulates

CRF and ACTH release, the production of glucocorticoids will eventually

terminate this release, thereby ensuring the maintenance of homeostasis.


et al., 1994). Corticosterone resulted in a small reduction in

IL-1 receptors only when injected subchronically. Saturation

studies after subchronic corticosteroid treatment did not

reveal modifications in the number and/or affinity of IL-1

receptors in the hippocampus. Since glucocorticoids in a

feedback loop inhibit the production of IL-1 induced by

LPS and IL-1 induces its own synthesis, the role of

glucocorticoids in the regulation of IL-1 autoregulatory

induction was examined in human monocytes at the level

of IL-1 protein production and mRNA accumulation (Paez

Pereda et al., 1996). Using recombinant IL-1 receptor

antagonist, it was established that endogenously produced

IL-1 affects the induction of IL-1h protein by LPS at the

level of mRNA expression. In addition, the inhibition of

LPS-stimulated IL-1h production and mRNA expression by

glucocorticoids (Dex and cortisol) reached the same level

with glucocorticoids alone or in combination with IL-1ra.

Of note, IL-1h mRNA induced by exogenously added IL-

1h was also inhibited by glucocorticoids, indicating that

glucocorticoids inhibit the autoregulatory loop of IL-1 in

LPS-stimulated monocytes and constitute a mechanism for

controlling IL-1 feedback stimulation (Paez Pereda et al.,

1996; Goujon et al., 1997; Plagemann et al., 1998).

In contrast, proinflammatory cytokines can reduce glu-

cocorticoid receptor translocation and function. Specifically,

several studies have found that cytokines induce a decrease

in glucocorticoid receptor (GR) function, as evidenced by

reduced sensitivity to glucocorticoid effects on functional

end points (Pariante et al., 1999). To investigate the poten-

tial mechanism(s) involved, the impact of the proinflam-

matory cytokine, IL-1a on (1) GR translocation from

cytoplasm to nucleus using GR immunostaining, (2) cyto-

solic radioligand GR binding and (3) GR-mediated gene

transcription in L929 cells stably transfected with the mouse

mammary tumor virus-chloramphenicol acetyltransferase

reporter gene was examined. L929 cells were treated with

IL-1a in the presence or absence of Dex. IL-1a inhibited

Dex-induced GR translocation and alone induced GR upre-

gulation. In addition, pretreatment with IL-1a followed by

Dex treatment led to inhibition of Dex-induced GR-medi-

ated gene transcription, whereas co-incubation of IL-1a plus

Dex inhibited Dex-induced GR-mediated gene activity; the

latter effect was reversed by the IL-1 receptor antagonist

(Pariante et al., 1999). These observations clearly suggested

that cytokines produced during an inflammatory response

may induce GR resistance in relevant cell types by direct

effects on the GR, thereby providing an additional pathway

by which the immune system can influence the HPA axis

(Daun et al., 2000; Elenkov et al., 2000).

Administration of LPS results in the activation of the

HPA axis (Perlstein et al., 1993; Brunetti et al., 1994; Takao

et al., 1994; Exton et al., 1995; Paez Pereda et al., 1995;

Grinevich et al., 2001). The mechanisms through which

LPS stimulates the HPA axis are not well understood,

however (Dunn, 1992; Ma et al., 2000). In initial studies

reported by Rivier et al. (1989), the hypothesis that LPS

increases plasma ACTH levels by releasing IL-1 was tested.

Two experimental tools reported to interfere with the bio-

logical activity of IL-1 were used: antibodies directed

against IL-1 receptors and a-melanocyte releasing hormone

(a-MSH) (Zelazowski et al., 1993; Papadopoulos and Ward-

law, 1999). In a first series of experiments, adult male mice

were injected with LPS, antibodies against IL-1 receptor, a-

MSH or LPS and either IL-1 antibodies or a-MSH. LPS

caused a marked increase in plasma ACTH levels. Both a-

MSH and the IL-1 receptor antibodies, while having no

effect by themselves, significantly blocked LPS-induced

ACTH release (Rivier et al., 1989). In a second series of

experiments, mice were injected intraperitoneally with

recombinant human IL-1a or IL-1h in the presence or

absence of a-MSH. While not altering ACTH secretion

induced by IL-1a, a-MSH interfered with the effect of IL-

1h (Rivier et al., 1989). These results suggested that LPS

activates the HPA axis through a mechanism involving the

activation of IL-1 receptors and that the effect of IL-1h, butnot IL-1a, on ACTH secretion can be partially blocked

by a-MSH. Therefore, LPS acts both at the level of the

brain and the gonads to stimulate the HPA axis, and inhibits

the hypothalamic–pituitary–gonadal (HPG) axis (Rivier,

1990).

Exogenously administered IL-1 mimics most of the

effects of LPS on pituitary activity. In addition, antibodies

against IL-1 receptors can interfere with LPS-induced

ACTH secretion, indicating that at least part of the ability

of LPS to alter endocrine functions appears to depend upon

endogenous IL-1 (Habu et al., 1998). Of interest, IL-1 and

IL-6 share a number of biological functions. Because IL-1

induces IL-6 in vivo, the extent to which IL-6 mediates the

effects of IL-1 has come under investigation (Mastorakos et

al., 1994). The stimulation of the HPA axis by IL-1 and IL-6

is recognized as a critical component of the inflammatory

response. In this respect, it was demonstrated that the

administration of IL-6 alone did not duplicate the stimula-

tory effect of IL-1a on ACTH release (Perlstein et al., 1991;

Connor et al., 1998). On the other hand, suboptimal

amounts of IL-1a and IL-6 synergized to induce an early

(30–60 min) ACTH response and produce a later (2–3 h)

response that was similar to the one observed after IL-1a

was administered alone, suggesting that the late response to

IL-1 may be dependent on synergy with the endogenous IL-

6 it induces systemically and in the CNS (including the

hypothalamus and the pituitary gland) (Perlstein et al.,

1991). Furthermore, to elucidate the mutual dependence

and contribution of individual cytokines in the course of

LPS-induced ACTH release, blocking antibodies to IL-1,

IL-6 and TNF were used (van der Meer et al., 1996).

Results, for example, demonstrated that anti-IL-6 antibody

abrogated ACTH induction throughout the course of LPS

challenge (Perlstein et al., 1993). In contrast, anti-IL-1

receptor and anti-TNF antibody, given individually, blocked

ACTH production after LPS challenge. Only combined

administration of these two antibodies diminished, but did


not eliminate, ACTH release, demonstrating that all three

inflammatory cytokines are obligatory for LPS-induced

elevation of plasma ACTH. In addition, these results sug-

gested that IL-1, IL-6 and TNF play different roles in LPS-

induced ACTH release (Mastorakos et al., 1993; Perlstein et

al., 1993). To further determine whether IL-1 acts within the

brain to mediate LPS-induced CRH gene expression in the

hypothalamic paraventricular nucleus (PVN), the effect of

administering the human IL-1 receptor antagonist (IL-1ra)

into the brain, a competitive inhibitor of IL-1, on CRH gene

expression in the PVN after systemic LPS treatment was

investigated. After the intraperitoneal administration of LPS,

the paraventricular CRH mRNA content was elevated; this

elevation could be completely abolished by central IL-1ra

pretreatment (Kakucska et al., 1993). In contrast, systemic

IL-1ra administration did not inhibit LPS-induced CRH

gene expression in the PVN, demonstrating that LPS stim-

ulates hypothalamic CRH by a mechanism that involves the

action of IL-1 within the CNS and may proceed independ-

ently of peripheral actions of IL-1 circulating in the blood-

stream (Ebisui et al., 1994). Of particular interest, the

redundant observations that cytokines synergize the stim-

ulatory effect of IL-1 on the HPA axis (Zhou et al., 1996).

That study examined the interaction between IL-6 and IL-1,

and between IL-6 and stress on the activation of the HPA

axis. For instance, co-administration of IL-6 with IL-1

resulted in synergistic stimulation of the HPA axis, as

determined by increased plasma levels of ACTH and CORT,

which were greater in rats that received both cytokines than

in rats receiving either cytokine alone (Zhou et al., 1996).

Concomitant administration of IL-6 with exposure to a

novelty stressor also synergistically stimulated the activation

of the HPA axis, as IL-6-treated rats subjected to novelty

stress had greater increases in plasma levels of ACTH and

CORT than vehicle-treated rats exposed to novelty stress or

rats receiving IL-6 alone. However, concomitant adminis-

tration of IL-6 did not significantly affect restraint stress-

induced elevation of plasma levels of ACTH and CORT,

although IL-6 tended to prolong restraint stress-induced

elevation of plasma levels of CORT. These findings indicate

a modulatory role for IL-6 stimulated HPA axis activity in

response to IL-1 or a novelty psychological stressor, but not

for restraint stress (del Rey et al., 1998). Although a

considerable amount of evidence has shown that physical

and psychological stress elevates the plasma IL-6 levels, the

physiological significance of such an elevation remains to

be elucidated (Nukina et al., 1998). In that study, in order to

determine whether the restraint stress-induced elevation of

plasma IL-6 contributes to the activation of the HPA axis

and whether or not such elevation can affect the inflamma-

tory processes, the plasma levels of ACTH, CORT, IL-1 and

TNF-a in mice pretreated with anti-IL-6 antibody (MP5-

20F3 monoclonal antibody) were compared with those in

mice pretreated with rat IgG (control antibody), both during

and after stress (Nukina et al., 1998). Both the anti-IL-6-

antibody- and control-antibody-pretreated mice showed the

same extent of plasma ACTH and CORT increases during

stress, and no significant difference was found between the

two groups of animals. On the other hand, the level of

plasma TNF-a in the anti-IL-6-treated animals was also

significantly higher than that in the control animals both

immediately after cessation of stress and after the cessation

of restraint. Plasma IL-1 activity, however, did not reach a

detectable level in either group of animals at any time point

examined, indicating that the restraint stress-induced eleva-

tion of plasma IL-6 negatively regulates the plasma TNF-a

levels and may thus contribute to the maintenance of

homeostasis (Nukina et al., 1998).

Further elaborating on the mechanisms related to LPS-

mediated regulation of the HPA axis, a role for hippocampal

mineralocorticoid (type I) receptor has been reported (Scho-

bitz et al., 1994). The authors studied the binding properties

of the corticosteroid receptor system, which mediates feed-

back inhibition of the HPA axis, in two brain areas and in

the pituitary gland in rats treated with LPS and recombinant

murine IL-1h. The binding properties of the corticosteroid

receptors were determined by Scatchard plot analyses of in

vitro cytosolic binding of the tritiated mineralocorticoid

receptor (MR) radioligand aldosterone and the tritiated GR

ligand RU-28362. Tissues were collected after administra-

tion of LPS, including a specific period for the depletion

of endogenous corticosterone. LPS treatment increased the

Kd of [3H]-aldosterone of the hippocampal MR and the

apparent maximum binding capacity (Bmax) of [3H]-aldos-

terone during a time interval when the concentration of

corticosterone, the endogenous ligand of both hippocampal

MR and GR, was elevated in the intact rat (Schobitz et al.,

1994). Thereafter, MR binding properties were not different

from vehicle-injected controls when in intact animals the

enhanced HPA activity subsided. GRs, determined by bind-

ing of [3H]-RU-28362, were not affected by LPS. Further-

more, IL-1 evoked an increase in the Kd of the hippocampal

MR and an increase in Bmax after injection into the lateral

cerebral ventricle. An autoradiographic procedure, in addi-

tion, revealed that the same treatment with IL-1 reduced the

retention of the tritiated endogenous MR ligand cortico-

sterone in all pyramidal cell layers and in the dentate gyrus

of the hippocampus, when a tracer dose of the steroid was

administered that gives rise to a concentration around the Kd

of the MR. This reduced in vivo retention of corticosterone

was predicted in view of the reduced affinity of hippo-

campal MRs, consistent with the hypothesis that an im-

paired feedback of the HPA axis via deficient hippocampal

MRs contributes to stimulate corticosterone secretion from

the adrenals during infection.

Another mechanism reported implicated histamine recep-

tors in LPS/IL-1-induced activation of the HPA axis and

ACTH release. LPS and LPS-derived cytokines stimulate

the release of histamine (HA). HA is a known hypothalamic

neurotransmitter and activates the HPA axis. To elucidate

the role of HA in LPS- and cytokine-induced ACTH release,

Perlstein et al. (1994) evaluated the effects of several HA


H1 and H2 receptor antagonists on the ACTH response to

LPS, IL-1a and HA in mice. Although all three of the H1

receptor antagonists administered [mepyramine (MEP),

diphenhydramine (DPH) or promethazine (PMZ)] were able

to block the 10-min ACTH response to HA, only PMZ (a

less selective H1 receptor antagonist than MEP) was able to

reduce the LPS- or IL-1a-induced ACTH responses. In

addition, ranitidine, a powerful and selective H2 receptor

antagonist, had little effect on the LPS- and IL-1a-induced

ACTH responses, while metiamide (MET), a much less

potent first-generation H2 receptor antagonist, substantially

diminished ACTH release. It was concluded that the greater

effectiveness of PMZ, in contrast to MEP or DPH, probably

relates to the ability of phenothiazine derivatives to inhibit

non-HA-dependent pathways involved in the stimulation of

the HPA axis by cytokines. In concert, Raab et al. (1999)

investigated the effects of IL-2 on endothelin levels and the

HPA axis. The authors determined the IL-6, big-endothelin

(ET), ET-1, ACTH, cortisol and AVP responses to intra-

venously and subcutaneously administered IL-2 in 8 cancer

patients in a randomized placebo controlled trial (all patients

enrolled had a World Health Organization performance

status of 1 or less and a Karnofsky Index of at least 80%).

IL-2 treatment significantly increased plasma big-ET levels

and endothelin-1 levels within 2 h, and this was followed by

an increase in ACTH and cortisol within 3 h. IL-6 levels

increased after IL-2 administration. IL-2, in addition, had

no detectable effect on AVP, blood pressure or heart rate

(Raab et al., 1999). These data clearly demonstrated that

the cytokine IL-2 could activate the human HPA axis in

vivo and, on the basis of the observed time kinetics and

in connection with findings from in vitro and animal

models, it was concluded that ET might be a link between

cytokines and CRH, most probably functioning as a cyto-

kine-induced neuromodulator controlling pituitary functions

(Fig. 4) (Dowdell et al., 1999).

2.2. IL-2 and HPA responses

The cytokine IL-2 exerts numerous effects within the

immune as well as the central nervous system and is thought

to serve as a humoral signal in their communication. A

major role for IL-2 has been noted in the regulation of the

HPA axis responses. Brain-derived or blood-borne IL-2 may

also control the activity of the HPA axis at various levels of

regulation. IL-2, for example, caused a dose-dependent

stimulation of AVP secretion from both the intact rat

hypothalamus in vitro and hypothalamic cell cultures (Hill-

house, 1994). IL-2, however, did not increase the secretion

of CRH in either preparation, nor did it prime the cells to

respond to a subsequent dose of IL-2. Both preparations,

nevertheless, were able to respond to known CRH secreta-

gogues, such as 5-HT and K+ (Hillhouse, 1994). This may

provide yet another line of communication between the

immune and neuroendocrine systems. In another study,

Hanisch et al. (1994) investigated whether persistently

elevated levels of central IL-2, which are associated with

several diseases or induced during immunotherapeutic use

Fig. 4. Scheme depicting systemic and cellular/molecular interplay between the HPA axis and the immune system in the regulation of glucocorticoid/cytokine

secretion and gene expression. Abbreviations: GR, glucocorticoid receptor; TF, transcription factors.


of this cytokine, could induce long-term activation of the

HPA axis. Adult male Sprague–Dawley rats received an

intracerebroventricular infusion of the recombinant cyto-

kine; control animals received heat-inactivated IL-2. IL-2

caused a significant increase in ACTH levels during the later

portion of the dark phase of the cycle. Plasma CORT

concentrations were significantly elevated over almost the

whole diurnal cycle. In addition, measurements of CORT-

binding globulin concentrations revealed IL-2-induced

decreases during the dark phase, resulting in a marked

increase in free CORT. Furthermore, after prolonged chronic

infusion, both groups of animals underwent restraint stress.

For instance, IL-2-treated animals showed stress-induced

increases in plasma ACTH and CORT that were not

significantly different from those of animals treated with

heat-inactivated IL-2. Along with the alteration of HPA

activity seen in the IL-2-treated animals, chronic delivery

of the cytokine caused periventricular tissue damage and

gliosis (Hanisch et al., 1994). Taken together, the data

reflected the capacity of IL-2 to modulate neuroendocrine

activity over an extended period of treatment (Raber et al.,

1998).

2.3. IL-3/IL-6 and HPA responses

Accumulating evidence indicate that IL-3 can activate

the HPA axis. For example, Weber et al. (1997) recently

evaluated the effect of IL-3 (and IL-6) on cortisol secretion

from adult human adrenocortical cells in primary culture.

IL-3 and IL-6 equipotently stimulated basal cortisol secre-

tion. The stimulatory effect was significant and maximum

cortisol levels were induced later. In contrast to ACTH,

which significantly induced cAMP levels in parallel to its

steroidogenic effect, IL-3 (or IL-6) had no significant effect

on cAMP (Weber et al., 1997). Furthermore, the authors

showed that specific inhibition of the cyclooxygenase path-

way by Indo completely blocked the steroidogenic effect of

IL-6 while the effect of IL-3 was not affected. In contrast,

co-incubation with nordihydroguaiaretic acid (NDGA), a

specific inhibitor of the lipoxygenase system, abolished IL-

3-stimulated steroidogenesis but had no effect on IL-6-

stimulated cortisol secretion, indicating that IL-3 and IL-6

directly stimulate the steroidogenesis at the adrenal level

through activation of different, cAMP-independent path-

ways. While the stimulatory effect of IL-6 on cortisol se-

cretion from adult human adrenocortical cells seems to be

mediated through the COX pathway, the effect of IL-3 on

adrenocortical cortisol secretion is dependent on the lip-

oxygenase pathway. Similarly, the effect of IL-3 and IL-6 on

cortisol secretion of bovine adrenocortical cells in primary

culture under serum-free conditions was further explored.

For instance, both IL-3 and IL-6 stimulated basal cortisol

secretion dose-dependently to a similar extent at a similar

time course (Michl et al., 2000). After incubation with IL-3

or IL-6, a maximum 4.1-fold increase of the cortisol

secretion was reached after 12 h. Co-incubation of IL-3

and IL-6 revealed, however, no significant synergism. To

elucidate a possible involvement of arachidonic acid metab-

olites in the signal transduction, IL-3 or IL-6 was co-

incubated with Indo or NDGA. Co-incubation with Indo

completely abolished the stimulatory effect of IL-6 but had

no effect on IL-3-stimulated cortisol secretion. In contrast,

specific inhibition of the lipoxygenase system by NDGA

blocked IL-3-stimulated steroidogenesis while the effect of

IL-6 was not affected. Neither IL-3 nor IL-6 altered cAMP

levels significantly, whereas ACTH significantly induced

cAMP levels in parallel to its steroidogenic effect. While the

stimulatory effect of IL-3 seems to be dependent on the

lipoxygenase pathway, the effect of IL-6 on adrenocortical

cortisol secretion is mediated through the COX pathway.

2.4. IL-4/IL-5/IL-10 and HPA responses

Glucocorticoids are widely used in the therapy of inflam-

matory, autoimmune and allergic diseases. As the end-

effectors of the HPA axis, endogenous glucocorticoids also

play an important role in suppressing innate and cellular

immune responses. The influence of Dex on IL-10 produc-

tion and the type 1 (T1)/type 2 (T2) T cell balance found in

rheumatoid arthritis (RA) was studied to determine a pos-

sible role for IL-4 in HPA-related responses to RA. Periph-

eral blood mononuclear cells (PBMNC) were isolated from

14 RA patients both before and 7 and 42 days after high

dose Dex pulse therapy (Verhoef et al., 1999). The ex vivo

production of IL-10, IFN-g (T1 cell) and IL-4 (T2 cell) by

PBMNC was assessed, along with parameters of disease

activity (erythrocyte sedimentation rate, C reactive protein,

Visual Analogue Scale, Thompson joint score). In addition,

the in vitro effect of Dex on PBMNC IL-10, IFN-g and IL-4

production was studied. It was reported that Dex pulse

therapy resulted in a rapid and sustained decrease in RA

disease activity. IL-10 production, in addition, increased

after Dex treatment and this was sustained for at least 6

weeks. A transient strong decrease in IFN-g was seen

shortly after corticosteroid treatment, while IL-4 only

decreased slightly. This led to an increased IL-4/IFN-g ratio.

Moreover, in vitro, IL-10 production was not detectable,

IFN-g and IL-4 decreased, but the effect was more pro-

nounced for IFN-g than for IL-4, which again resulted in an

increased IL-4/IFN-g ratio. Dex therapy in RA patients,

therefore, might lead to a rapid, clinically beneficial effect:

the upregulation of IL-10 production could be involved in

the prolonged clinical benefit. The strong immunosuppres-

sive effect is most evident in the decrease in IFN-g and is

therefore accompanied by a relative shift towards T2 cell

activity (Verhoef et al., 1999). In vitro evaluation showed

that this shift in T cell balance was a direct effect of Dex and

thus independent of the HPA axis. In concert, the anti-

inflammatory activity of corticosteroids has prompted the

exploration of their use in the treatment of allergic rhinitis,

which involves TL-4 and IL-5. The development of intra-

nasal steroids has resulted in several agents with quick


actions, localized effects, and great efficacy in the treatment

of seasonal allergic rhinitis and the prophylactic manage-

ment of perennial rhinitis (Lumry, 1999). The survey

revealed that mometasone furoate, a new inhaled steroid

with topical activity, had the greatest binding affinity for the

GR, followed by fluticasone propionate, budesonide, triam-

cinolone acetonide and Dex. Mometasone furoate also has

strong anti-inflammatory activity, with IL-4 and IL-5 inhib-

ition activities equivalent to those of fluticasone propionate.

Clinically, both mometasone furoate and fluticasone propi-

onate appear to be well tolerated, to have quick onsets of

action and to be equivalent in efficacy in the treatment of

seasonal allergic and perennial rhinitis (Lumry, 1999). Of

the intranasal steroids currently available, mometasone

furoate has been shown to have the least systemic avail-

ability and, consequently, is expected to have the fewest

systemic side effects. Of note, some suppression of over-

night cortisol levels has been reported with fluticasone

propionate (indicative of the HPA axis suppression).

The proinflammatory cytokines, IL-1 and TNF-a, were

among the first to be recognized in this regard. A modulator

of these cytokines, IL-10, has been shown to have a wide

range of activities in the immune system. IL-10 is produced

in pituitary, hypothalamic and neural tissues in addition to

lymphocytes (Smith et al., 1999). IL-10 enhances CRF and

ACTH production in hypothalamic and pituitary tissues,

respectively. Further downstream in the HPA axis endoge-

nous IL-10 has the potential to contribute to regulation of

glucocorticosteroid production both tonically and following

stressors. Evidence indicated that IL-10 might be an impor-

tant endogenous regulator in HPA axis activity and in CNS

pathologies. Thus, in addition to its more widely recognized

role in immunity, as anti-inflammatory cytokine, IL-10’s

neuroendocrine activities point to its role as an important

regulator in communication between the immune and neuro-

endocrine systems (Fig. 3).


Recent studies have indicated that IL-12 promotes Th1

cell-mediated immunity, while IL-4 stimulates Th2 humoral-

mediated immunity (Franchimont et al., 2000). The regula-

tory effect of glucocorticoids on key elements of IL-12 and

IL-4 signaling were further examined. On the analysis of the

effect of Dex on IL-12-inducible genes, it was shown that

Dex inhibited IL-12-induced IFN-g secretion and IFN reg-

ulatory factor-1 expression in both NK and T cells (Franchi-

mont et al., 2000). This occurred even though the level of

expression of IL-12 receptors and IL-12-induced Janus

kinase phosphorylation remained unaltered. However, Dex

markedly inhibited IL-12-induced phosphorylation of Stat-4

without altering its expression. This was specific, as IL-4-

Fig. 5. The inflammatory response and the HPA axis. Some of the effects of the inflammatory response on the neuroendocrine system are illustrated. A stimulus

such as trauma, stress, immune challenge, or bacterial, viral and fungal toxins acts to provoke the inflammatory process. Inflammatory cells respond by

secreting inflammatory mediators such as cytokines. A profound process of inflammation ensues and propagates itself with the auto-induction (autocrine) of

inflammatory mediators, including cytokines, eiconsanoids, platelet-activating factor, neuropeptides and various other mediators. These agents, particularly

inflammatory cytokines, act either directly or indirectly to increase the production of releasing hormones in the hypothalamus (HPA axis), pituitary hormones,

cortisol and catecholamines. In addition, the liver participates in this inflammatory–HPA axis by releasing acute-phase proteins. Abbreviations: ACTH,

adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; LT, leukotriene; IL, interleukin; LHRH, luteinizing hormone-releasing hormone; PAF,

platelet-activating factor; PGE2, prostaglandin; TSH, thyroid-stimulating hormone; TNF, tumor necrosis factor.


induced Stat-6 phosphorylation was not affected, and medi-

ated by the glucocorticoid receptor, as it was antagonized by

the glucocorticoid receptor antagonist RU-486 (Franchimont

et al., 2000). Moreover, transfection experiments showed

that Dex reduced responsiveness to IL-12 through the

inhibition of Stat-4-dependent IFN regulatory factor-1 pro-

moter activity. It was concluded that blocking IL-12-induced

Stat-4 phosphorylation, without altering IL-4-induced Stat-6

phosphorylation, appears to be a new suppressive action of

glucocorticoids on the Th1 cellular immune response and

may help explain the glucocorticoid-induced shift toward the

Th2 humoral immune response (Fig. 4).


Vertebrates achieve internal homeostasis during infec-

tion or injury by balancing the activities of proinflamma-

tory and anti-inflammatory pathways. The CNS regulates

systemic inflammatory responses to LPS, for instance,

through humoral mechanisms (Fig. 4). Activation of affer-

ent vagus nerve fibers by LPS or cytokines specifically

stimulates HPA anti-inflammatory responses. In this

respect, it was described that a previously unrecognized,

parasympathetic anti-inflammatory pathway by which the

brain modulates systemic inflammatory responses to LPS is

active at the level of the HPA axis (Borovikova et al.,

2000). Acetylcholine, the principle vagal neurotransmitter,

significantly attenuated the release of proinflammatory

cytokines, including IL-18, but not the anti-inflammatory

cytokine IL-10, in LPS-stimulated human macrophage

cultures. Furthermore, direct electrical stimulation of the

peripheral vagus nerve in vivo during lethal endotoxemia

in rats inhibited TNF synthesis in liver, attenuated peak

serum TNF amounts, and prevented the development of

shock (Borovikova et al., 2000). Similarly, increased para-

sympathetic tone and acetylcholine, the principle vagal

neurotransmitter, significantly attenuate the release of

TNF-a, IL-1h, IL-6 and IL-18 (Das, 2000). Scheme

depicting a close relationship between the inflammatory

process and the HPA axis is shown in Fig. 5, and the roles

of CRF and corticosteroids (glucocorticoids) in a variety of

body mechanisms are depicted in Fig. 6.

3. HPA interactions and oxidative stress: a role for the

transcription factor NF-KB

The mammalian stress response evokes a series of neuro-

endocrine responses that activate the HPA axis and the SNS

(Fig. 3). Coordinated interactions between stress response

systems, occurring at multiple levels including the brain,

pituitary gland, adrenal gland and peripheral tissues, are

required for the maintenance of homeostatic plateau. Adap-

tation to stress evokes a variety of biological responses,

including activation of the HPA axis and synthesis of a panel

of stress-response proteins at cellular levels (Fig. 5). For

example, expression of thioredoxin (TRX), a non-thiol anti-

oxidant, is significantly induced under oxidative conditions.

In this regard, Makino et al. (1996) demonstrated that either

antisense TRX expression or cellular treatment with hydro-

gen peroxide (H2O2) negatively modulated GR function and

decreased glucocorticoid-inducible gene expression. In addi-

Fig. 6. The effects of CRF and corticosteroids (glucocorticoids) on a variety of body mechanisms. These wide-ranging effects underscore the significance of

HPA axis interactions and the mechanisms involved.


tion, impaired cellular response to glucocorticoids is rescued

by overexpression of TRX, most possibly through the func-

tional replenishment of the GR (Makino et al., 1996). More-

over, not only the ligand-binding domain but also the DNA

binding domain of the GR was also suggested to be a direct

target of TRX. Together, these observations presented con-

clusive evidence showing that cellular glucocorticoid re-

sponsiveness is coordinately modulated by redox state and

TRX level and, thereby, it was proposed that cross talk

between neuroendocrine control of stress responses and

cellular antioxidant systems may be essential for mammalian

adaptation processes.

Employing primary neurons and clonal cells, Lezoualc’h

et al. (2000) demonstrated that CRH has a neuroprotective

activity in CRH-receptor type 1 (CRH-R1)-expressing neu-

rons against oxidative cell death. The protective effect of

CRH was blocked by selective and nonselective CRH-R1

antagonists and by protein kinase A (PKA) inhibitors. In

addition, overexpression of CRH-R1 in clonal hippocampal

cells lacking endogenous CRH-receptors established neuro-

protection by CRH. The activation of CRH-R1 and neuro-

protection were accompanied by an increased release of

non-amyloidogenic soluble Ah precursor protein, character-

istic of Alzheimer’s (Pedersen et al., 2001). At the molecular

level, CRH caused the suppression of the DNA-binding

activity and transcriptional activity of the oxygen- and

reduction–oxidation (redox)-sensitive transcription factor,

nuclear factor (NF)-nB (Haddad et al., 2000, 2001c, 2002c;

Haddad, 2002). Suppression of NF-nB by overexpression of

a super-repressor mutant form of inhibitory-nB (InB)-a, aspecific inhibitor of NF-aB, led to protection of the cells

against oxidative stress (Lezoualc’h et al., 2000; Haddad et

al., 2001c). These observations strongly demonstrated a

novel cytoprotective effect of CRH that is mediated by

CRH-R1 and downstream by suppression of NF-nB, andindicate CRH as an endogenous protective neuropeptide

against oxidative cell death in addition to its function in the

HPA system. Moreover, the protective function of CRH

proposes a molecular link between oxidative stress-related

degenerative events and the CRH-R1 system. Further elab-

orating on the role of transcriptional regulation in HPA

responses, dysregulation of the serotonergic system and

abnormalities of the HPA axis function have been impli-

cated to be involved in neuropsychiatric disorders (Wissink

et al., 2000). Corticosteroid hormones in a variety of animal

models suppress serotonin-1A receptors. This effect may

play a central role in the pathophysiology of depression.

However, little is known about the molecular mechanism

underlying this suppressive effect of CORT. In this respect,

Wissink et al. (2000) showed by functional analysis of the

promoter region of the rat serotonin-1A receptor gene that

two NF-nB elements in the promoter contribute to induced

transcription of the rat serotonin-1A receptor gene. Further-

more, it was shown that CORT represses this NF-nB-mediated induction of transcription. Remarkably, only the

GR and not the MR was able to mediate this repressive

effect of CORT, thus arguing that negative cross-talk

between the GR and NF-nB may provide a basis for the

molecular mechanism underlying the negative action of

CORT on serotonin signaling in the brain (Lohrer et al.,

2000; van Leeuwen et al., 2001).

4. HPA interactions and oxidative stress: a role for

gaseous transmitters

Recent work has demonstrated that the brain has the

capacity to synthesize impressive amounts of the gases nitric

oxide (NO) and carbon monoxide (CO) (Rivier, 2001,

2002). There is growing evidence that these gaseous mol-

ecules function as novel neural messengers in the brain

(Brann et al., 1997). Abundant evidence is presented which

suggests that NO has an important role in the control of

reproduction due to its ability to control GnRH secretion

from the hypothalamus. NO potently stimulates GnRH

secretion and also appears to mediate the action of one of

the major transmitters controlling GnRH secretion, gluta-

mate. Evidence suggests that NO stimulates GnRH release

due to its ability to modulate the heme-containing enzyme,

guanylate cyclase, which leads to enhanced production of

the second messenger molecule, cGMP (Brann et al., 1997).

A physiological role for NO in the preovulatory LH surge

was also evidenced by findings that inhibitors and antisense

oligonucleotides to nitric oxide synthase (NOS) attenuate

the steroid-induced and preovulatory luteinizing hormone

(LH) surge. CO may also play a role in stimulating GnRH

secretion as heme molecules stimulate GnRH release in

vitro, an effect that requires heme oxygenase activity and is

blocked by the gaseous scavenger molecule, hemoglobin.

Evidence also suggests that NO act to restrain the HPA axis,

as it inhibits HPA stimulation by various stimulants such as

IL-1, vasopressin (VP) and inflammation. This effect fits a

proinflammatory role of NO as it leads to suppression of the

release of the anti-inflammatory corticosteroids from the

adrenal. Although not as intensely studied as NO, CO has

been shown to suppress stimulated CRH release and may

also function to restrain the HPA axis (Rivier, 1998).

Evidence implicating NO in the control of prolactin (PRL)

and GH secretion is plausible, as is the possible role of NO

acting directly at the anterior pituitary. Taken as a whole, the

current data suggest that the diffusible gases, NO and CO,

act as novel transmitters in the neuroendocrine axis and

mediate a variety of important neuroendocrine functions. To

recapitulate, NO is an unusual chemical messenger. NO

mediates blood vessel relaxation when produced by endo-

thelial cells. When produced by macrophages, NO contrib-

utes to the cytotoxic function of these immune cells. NO

also functions as a neurotransmitter and neuromodulator in

the central and peripheral nervous systems. The effects on

blood vessel tone and neuronal function form the basis for

an important role of NO on neuroendocrine function and

behavior. NO mediates hypothalamic portal blood flow and,


thus, affects OT and VP secretion; furthermore, NO medi-

ates neuroendocrine function in the HPG and HPA axes. NO

influences several motivated behaviors including sexual,

aggressive and ingestive behaviors. NO also influences

learning and memory (Nelson et al., 1997). NO, thus, is

emerging as an important chemical mediator of neuroendo-

crine function and behavior.

NOS, the enzyme responsible for NO formation, is found

in hypothalamic neurons containing OT, VP and, to a lesser

extent, CRF (Rivier and Shen, 1994; Bugajski et al., 1997).

Because NO is reported to modulate endocrine activity, the

hypothesis that endogenous NO participates in ACTH

released by various secretagogues was investigated in vivo.

In the adult male rat, the intravenous injection of IL-1h, VPand OT increased plasma ACTH and CORT levels (Rivier

and Shen, 1994). Pretreatment with the L-form, but not the D-

form, of NN-nitro-L-arginine-methylester (L-NAME), a spe-

cific inhibitor of NOS, markedly augmented the effects of

these secretagogues. Blockade of NOS activity also caused

significant extensions of the duration of action of IL-1h, VPand OT. In contrast, L-NAME did not significantly alter the

stimulatory action of peripherally injected CRF, or centrally

administered IL-1h. In addition, administration of L-argi-

nine, but not D-arginine, used as a substrate for basal NO

synthesis and which did not by itself alter the activity of the

HPA axis, blunted IL-1-induced ACTH secretion and

reversed the interaction between L-NAME and IL-1h (Rivier

and Shen, 1994). Then, following prenatal alcohol exposure,

immature offspring showed blunted ACTH released in

response to the peripheral administration of IL-1h. Furtherstudies were conducted to investigate the role of changes

in corticosteroid feedback (measured by altered adrenal re-

sponses to ACTH), CRF content of the median eminence

(ME) and the influence of endogenous NO. For instance, the

injection of several doses of ACTH failed to indicate

measurable differences between the corticosterone responses

of offspring born to dams fed ad libitum [control (C)], pair-

fed (PF), or fed alcohol [ethanol (EtOH)]. CRF content in

the ME, taken as an index of the amount of releasable

peptide, showed a small, but statistically significant, de-

crease following prenatal alcohol exposure. A comparable

change, however, was also noted in PF rats. As expected, the

subcutaneous injection of IL-1h induced smaller increases in

plasma ACTH levels of EtOH than C pups. The response of

PF animals was intermediate between that of EtOH and C

rats. It was also observed that inhibition of NO formation by

the administration of the arginine derivative L-NAME aug-

mented ACTH secretion in all three experimental groups and

reversed the decreased corticotrophs’ response to IL-1hcaused by prenatal alcohol. Taken together, these results

suggested that the ability of prenatal alcohol exposure to alter

ACTH released by immature pups in response to blood-

borne IL-1h is probably not mediated through changes in

adrenal responsiveness. In concert, Tsuchiya et al. (1997)

recently indicated that L-NAME could modify the stress-

induced ACTH and corticosterone responses, because it was

found that immobilization-induced stress increases NOS

mRNA and protein levels and enzyme activity in the adrenal

cortex. The physiological significance of these phenomena,

however, remains unknown. The NOS enzyme activity in the

adrenal cortex of rats pre-injected with saline was signifi-

cantly higher than that in the nonstressed controls. In

addition, pre-injection of L-NAME almost completely abol-

ished the activity. This dose of L-NAME maintained a

significantly elevated plasma corticosterone level, whereas

the plasma corticosterone level in rats pre-injected with

saline returned to the basal level at the same time point.

Further, plasma ACTH level in L-NAME-pretreated rats was

higher than that in those pretreated with saline, but the

difference was not significant. This dose of L-NAME did

not influence plasma ACTH or corticosterone levels under

resting conditions without stress (Tsuchiya et al., 1997; Kim

and Rivier, 1998, 2000). These findings suggest that the

stress-induced increase in NO synthesis in the adrenal cortex

can modify the stress-induced corticosterone response to

facilitate the recovery from the elevated CORT secretion

by stress in the adrenal cortex to the resting basal level. As

indicated, the immobilization stress can cause changes in the

enzyme activity and gene expression of neuronal NOS in the

hypothalamus, pituitary and adrenal gland in vivo. In this

regard, NOS enzyme activity was measured as the rate of

[3H]-arginine conversion to citrulline and the level of NOS

mRNA signal were determined using in situ hybridization

and image analysis. NOS-positive cells were also visualized

using nicotinamide adenine dinucleotide phosphate-diaphor-

ase (NADPH-diaphorase) histochemistry and by immuno-

histochemistry. A significant increase of NOS enzyme

activity in the anterior pituitary, adrenal cortex and adrenal

medulla was observed in the stressed animals, as compared

to nonstressed control rats (Kishimoto et al., 1996). Upre-

gulation of NOS mRNA expression in anterior pituitary and

adrenal cortex was already detectable after stress. The NOS

mRNA signals in PVN increased after the stress imposed. In

addition, an increase of NOS enzyme activity in adrenal

medulla after immobilization posited by far longer than in

the adrenal cortex and anterior pituitary, suggesting that

psychological and/or physiological stress causes NO release

in the HPA axis and in the sympatho–adrenal system

(Kishimoto et al., 1996). It was proposed that NO may

modulate a stress-induced activation of the HPA axis and

the sympatho–adrenal medullary system (Fig. 3). The differ-

ent duration of stress-induced NOS activity in HPA axis and

the adrenal medulla may suggest NO synthesis is controlled

by separate mechanism in the two HPA and the sympatho–

adrenal systems (Kim and Rivier, 1998; Prevot et al., 2000;

Shan and Krukoff, 2001).

On the molecular mechanisms reported for the action of

NO with the HPA axis, Lee et al. (1999) investigated the

effect of the intracerebroventricular injection of the NO

donor 3-morpholino-sydnonimine (SIN-1) on the release

of ACTH and the neuronal response of hypothalamic

neurons responsible for this release. Rats that were admin-


istered SIN-1 showed significant elevations in plasma

ACTH levels, a response that was virtually abolished by

antibodies against CRF and significantly blunted by VP

antiserum. SIN-1 also upregulated heteronuclear (hn) tran-

scripts for CRF and VP and mRNA levels for the immediate

early gene NGFI-B and for CRF-R1 in the parvocellular

portion of the PVN of the hypothalamus (Lee et al., 1999).

Blockade of prostaglandin synthesis with ibuprofen did not

alter the ACTH or the PVN response to SIN-1. The central

nucleus of the amygdala and the supraoptic nucleus, regions

that are involved in autonomic adjustments to altered

cardiovascular activity, also responded to SIN-1 with ele-

vated NGFI-B mRNA levels. However, the only change in

mean arterial blood pressure caused by this NO donor was a

transient and modest increase. Thus, NO stimulates the

activity of PVN neurons that control the HPA axis. It must

be noted, however, that these results do not allow the

determination whether this effect was direct or mediated

through PVN afferents. This, however, should help resolve

the controversy generated by the use of isolated brain tissues

to investigate the net effect of NO on hypothalamic peptide

production. Another study was undertaken to investigate the

mechanisms involved in SIN-1-induced activation of the

HPA axis in urethane- and a-chloralose-anesthetized rats

(Okada et al., 2002). Intracerebroventricularly administered,

SIN-1 elevated plasma levels of CORT. Pretreatment with

phentolamine, an a-adrenoceptor antagonist, attenuated the

elevation of plasma CORT evoked by SIN-1, but sotalol, an

h-adrenoceptor antagonist, was without effects. The same

doses of SIN-1 also increased the release of noradrenaline in

PVN measuring microdialysis technique, and this increase

was abolished by tetrodotoxin administered into the perfu-

sion solution of the PVN. Furthermore, pretreatment with

Indo abolished the SIN-1-induced elevations of both nora-

drenaline in the PVN and plasma corticosterone. These

results suggest that SIN-1 activates central noradrenergic

neurons innervating the PVN by prostaglandin-mediated

mechanisms. Released noradrenaline in the PVN elevates

plasma levels of CORT via an activation of the central a-

adrenoreceptors in vivo.

5. Conclusions and future prospects

The HPA system communicates bidirectionally with

neuro– immune–endocrine interactions (Figs. 3 and 7)

(Roy et al., 1990; Janowsky et al., 1983). The neuro–

immune–endocrine interface is mediated by cytokines act-

ing as auto/paracrine or endocrine factors regulating pitui-

tary development, cell proliferation, hormone secretion and

feedback control of the HPA axis. Soluble products that

appear to transmit information from the immune compart-

ments to the CNS act as immunotransmitters and function in

immunomodulatory neuroendocrine circuits. The relative

importance of systemically and locally produced cytokines

in achieving these responses and their precise sites of action

have been the focus of a burgeoning number of investiga-

tions over the past few decades. There is now cumulating

evidence that there are important interactions between the

immune and neuroendocrine systems, which may explain, in

Fig. 7. Neurochemical mechanisms and their site of action, including the HPA axis. ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor;

LC, locus ceruleus; NE, norepinephrine.


part, some of the effects on growth, thyroid, adrenal and

reproductive functions which occur in the pathophysiology

of acute and chronic disease.

Acknowledgements

The author’s own publications therein cited are, in part,

financially supported by the Anonymous Trust (Scotland),

the National Institute for Biological Standards and Control

(England), the Tenovus Trust (Scotland), the UK Medical

Research Council (MRC, London), the Wellcome Trust

(London) (Dr. Stephen C. Land, Tayside Institute of Child

Health, University of Dundee, Scotland, UK) and the

National Institutes of Health (NIH; Bethesda, USA)

(Professor Philip E. Bickler, Department of Anesthesia and

Perioperative Care, University of California, San Francisco,

California, USA). The work of the author was performed at

the University of Dundee, Scotland, UK. This review was

written at UCSF, California, USA. Dr. John J. Haddad held

the Georges John Livanos prize (London, UK) under the

supervision of Dr. Stephen C. Land and the NIH award

fellowship (California, USA) under the supervision of

Professor Philip E. Bickler. The author also appreciatively

thanks Jennifer Schuyler (Department of Anesthesia and

Perioperative Care) for her excellent editing and reviewing

of this manuscript. I also thank my colleagues at UCSF (San

Francisco, California, USA) and the American University of

Beirut (AUB, Beirut, Lebanon) who have criticized the work

for enhancement and constructive purposes.

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