Hormonal regulation of immune function

To give an idea of the incredible extent to which the neuro-endocrine system is important in the regulation of immunefunction, Table 1 lists just some of the known neuroendocrinefactors and their effects on immune cells.

Activation of the hypothalamic–pituitary–adrenal (HPA)axis in response to stress results in secretion of corticotrophin-releasing factor (CRF) from the hypothalamus. Corticotrophin-releasing factor stimulates the pituitary to release adreno-corticotrophic hormone (ACTH) and this in turn stimulatesglucocorticoid secretion by the adrenals. Glucocorticoidsecretion is regulated by negative feedback, cortisol inhibit-ing the secretion of both CRF and ACTH. The glucocorticoidsare among the best-characterized hormones, possessing powerful and far-reaching immunoregulatory activity. Gluco-corticoids exert powerful anti-inflammatory actions, inhibit-ing inflammatory mediators including cytokines, phospholipidproducts, proteases and oxygen metabolites.1 They down-regulate cytokine expression by binding to, and activating,negative regulatory elements in the promoters of cytokinegenes,2–4 and by inducing production of IκB-α, a protein thatbinds and neutralizes the cytokine transcription factor nuclearfactor-κB (NF-κB).5 Cytokines downregulated by gluco-corticoids include IL-1,6 IL-2 and IFN-γ,2 IL-3, GM-CSF andTNF-α,7 IL-4,8 IL-63 and IL-8.4 Interestingly, glucocorticoidsinduce release of macrophage inhibitory factor (MIF), aninflammatory cytokine, from macrophages and T cells.9

Therefore, a primary role of MIF may be to counter the anti-inflammatory effects of glucocorticoids.10

In contrast to their suppression of cell-mediated immu-nity, glucocorticoids enhance immunoglobulin production.11

Furthermore, at glucocorticoid levels that inhibit IL-2 pro-duction, IL4 production is increased.12 Glucocorticoids biasin favour of the development of T cells that produce Th2cytokines.13 T cells primed in the presence of low concentra-tions of glucocorticoids preferentially express IL-10 at levelsup to fivefold higher than in the absence of beclamethasone.14

Glucocorticoids also increase TGF-β mRNA expression byboth unstimulated and PHA-stimulated T cells.15 The propen-sity of glucocorticoids to increase production of IL-4, IL-10and TGF-β is consistent with their imparting a selective biastowards Th2 responses. Memory T cells are 100-fold less sensitive than naive T cells to inhibition by glucocorticoids,14,16

raising the possibility that glucocorticoids have a greater rolein regulating primary than secondary immune responses.

Other HPA hormones have immunoregulatory actions.Corticotrophin-releasing hormone (CRH) inhibits endotoxin-stimulated production of IL-1 and IL-6 by human monocytesand ACTH suppresses IFN-γ production by human lympho-cytes.17 Growth hormone (GH) activates human macrophagesand primes monocytes for enhanced H

2O

2release.18 When

given to hypopituitary animals, growth hormone augmentsantibody synthesis and skin graft rejection.19 Similarly, pro-lactin enhances macrophage function. Reduced prolactinrelease in response to bromocryptine administration is asso-ciated with suppression of macrophage tumouricidal activity,impaired IFN-γ production and depressed T-cell prolifera-tion.20 These defects are all reversed by administration of exogenous prolactin.20 Other pituitary hormones with immuno-regulatory activity include follicle-stimulating hormone andluteinizing hormone21 and thyroid-stimulating hormone.22

It is not only hormones that originate in the HPA axis that have immunoregulatory activity. Melatonin as secretedby the pineal gland sensitizes monocytes to LPS activation

Immunology and Cell Biology (2001) 79, 350–357

Special Feature

Towards a unified model of neuroendocrine–immune interaction

NIKOLAI PETROVSKY

Autoimmunity Research Unit, Canberra Clinical School, University of Sydney and Division of Science and Design,University of Canberra, Canberra, Australian Capital Territory, Australia

Summary Although the neuroendocrine system has immunomodulating potential, studies examining the relationship between stress, immunity and infection have, until recently, largely been the preserve of behaviouralpsychologists. Over the last decade, however, immunologists have begun to increasingly appreciate that neuro-endocrine–immune interactions hold the key to understanding the complex behaviour of the immune system in vivo. The nervous, endocrine and immune systems communicate bidirectionally via shared messenger moleculesvariously called neurotransmitters, cytokines or hormones. Their classification as neurotransmitters, cytokines orhormones is more serendipity than a true reflection of their sphere of influence. Rather than these systems beingdiscrete entities we would propose that they constitute, in reality, a single higher-order entity. This paper reviewscurrent knowledge of neuroendocrine–immune interaction and uses the example of T-cell subset differentiation toshow the previously under-appreciated importance of neuroendocrine influences in the regulation of immune function and, in particular, Th1/Th2 balance and diurnal variation there of.

Key words: cytokine, immune, neuroendocrine, regulation, T-cell subsets.

Correspondence: Assoc. Prof. N Petrovsky, NHSC AutoimmunityResearch Unit, The Canberra Hospital, PO Box 11, Woden, ACT2606, Australia. Email: nikolai.petrovsky@anu.edu.au

Received 4 May 2001; accepted 4 May 2001.

and enhances IL-123 and IFN-γ production.24 Melatonin,administered in vivo, antagonizes the immunosuppressiveeffects of cortisol and prevents cortisone-induced thymicatrophy.25 Melatonin also regulates IL-12 and nitric oxideproduction by primary cultures of rheumatoid synovialmacrophages and the THP-1 monocytic cell line, suggestinga possible role in rheumatoid arthritis.26 Other hormones with

immunoregulatory activity (summarized in Table 1) includedehydroepiandrosterone sulfate (DHEAS),27–29 β-endorphin,30

substance P31,32 and vasoactive intestinal polypeptide.33,34

Even leptin has been implicated to have a role in immune regulation as part of the adaptation to fasting.35

Some hormones have direct effects on cytokine or cyto-kine receptor gene expression. For example, 17β-oestradiol

Neuroendocrine–immune interactions 351

Table 1 Neuroendocrine factors and their effects on immune function

Hormone Cytokine/immune function

α-endorphin Inhibits Ig productionα-MSH Suppresses DTH and inhibits IL-1 and IL-2 production via inhibition of NF-κBAcetylcholine Stimulates T and NK cells and increases IFN-γ productionACTH Inhibits IFN-γ production and Ig production and blocks macrophage activation by IFN-γAdrenaline Inhibits IL-1 and IL-2 productionAngiotensin 2 Enhances IFN-γ productionβ-endorphin Enhances IFN-γ production and NK-cell mediated cytotoxicity

Inhibits T-cell proliferationcAMP Enhances IL-4 and IL-5 production

Inhibits IL-2 productionCalcitonin-gene-related peptide Increases T-cell adhesion and stimulates IL-2, IL-4 and IFN-γ productionCatecholamines Enhance Ig production. Decrease the number of T and NK cells in the peripheral circulation and

inhibit NK cellsCortisol Inhibits IFN-γ, IL-2, IL-6 and TNF-α

Enhances IL-4 and TGF-β productionEnhances immune cell expression of IL-1, IL-2, IL-6 and IFN-γ receptors

CRH Activates macrophagesInhibits IL-1 and IL-6 production

DHEAS Enhances IFN-γ production and T-cell proliferationGrowth hormone Activates macrophages and enhances H

2O

2production

Gonadotropin-releasing hormone Increases IL2R expression, T- and B-cell proliferation and serum IgHistamine Inhibits IL-12, TNF and IFN-γ and enhances IL-10 productionInhibin Inhibits IFN-γ productionIGF1 and IGF2 Enhance PBMC proliferationLH Enhances IL-2 stimulated T-cell proliferationMacrophage inhibitory factor Blocks glucocorticoid inhibition of T-cell proliferation and cytokine productionMelatonin Enhances IL-1, Il-2, IL-6 and IFN-γ productionMet-enkephalin Enhances antigen-specific proliferationNerve growth factor Enhances B-cell proliferation, IL-6 production, IL-2 receptor expression and Ig-G4 synthesisNeuropeptide Y Increases T-cell adhesion and stimulates IL-2, IL-4 and IFN-γOestrogen Enhances T-cell proliferation and activity IFN-γ gene promoterOxytocin Enhances IFN-γ productionPGE

2Inhibits IL-2 production

Progesterone Enhances IL-4 production and CD30 expressionProlactin Enhances T-cell proliferation, IFN-γ, IL-2 receptor expression and macrophage functionSerotonin Inhibits T-cell proliferation and IFN-γ induced HLA class II expression

Enhances NK cytotoxicitySomatostatin Inhibits T-cell proliferation and IFN-γ productionSubstance P Enhances T-cell proliferation and IL-1, IL-6, TNF and IFN-γ production and macrophage actionTestosterone Enhances IL-10 productionTSH Enhances IL-2, GM-CSF and Ig productionThyroxine Activates T cells1,25 Vitamin D3 Inhibits IL-2 and IFN-γ

Enhances IL-4 productionVasopressin Enhances IFN-γ productionVIP Inhibits T-cell proliferation and IL-12

Enhances IL-5 and cAMP production

ACTH, adrenocorticotrophic hormone; CRH, corticotrophin-releasing hormone; DHEAS, dehydroepiandrosterone sulfate; DTH, delayed typehypersensitivity; IGF, insulin-like growth factor; LH, luteinizing hormone; MSH, melanocyte-stimulating hormone; NF-κB, nuclear factor-κB;TSH, thyroid stimulating hormone; VIP, vasoactive intestinal polypeptide.

markedly increases activity of the IFN-γ gene promoter inlymphoid cells.36 Similarly, progesterone induces transientIL-4 gene expression in established TH1 clones,28 whileglucocorticoids upregulate immune cell expression of recep-tors for IL-1, IL-2, IL-6 and IFN-γ.37

Cytokine regulation of neuroendocrine function

In keeping with the bidirectional nature of the neuro-endocrine and immune pathways, cytokines also influenceneuroendocrine function. This was highlighted by the earlyfinding that corticosterone levels are increased several foldduring the primary immune response of rats to sheep redblood cells. Immune influences on neuroendocrine functionare now known to be principally mediated by cytokines,receptors for which are widely expressed throughout theneuroendocrine system.

The first cytokines shown to have neuroendocrine effectswere the interferons, administration of which increasessteroidogenesis. Subsequently, IL-1, IL-2 or IL-6, IFN-β,IFN-γ, leukaemia inhibitory factor (LIF) and TNF-α havebeen shown to elevate plasma ACTH and glucocorticoidlevels in both laboratory animals and humans.38,39,40,41 IL-1, -2 and -6 and TNF-α all directly stimulate cortisol secretionby adrenal cells in culture and IL-1 and -6 stimulate cultured pituitary cells to produce ACTH and β-endorphin.42

The glucocorticoid-inducing effect of IL-1, in vivo, is abrogated by the administration of CRH antagonists. This sug-gests that the principal pathway by which cytokines induceglucocorticoid secretion is via stimulation of hypothalamicCRH secretion rather than via direct stimulation of adrenalglucocorticoid production. Interestingly, IL-2 is the mostpotent secretagogue for ACTH currently identified and ismore active on a molar basis than CRH, the classical regulator of ACTH secretion.43 This explains the elevation ofcortisol levels observed in cancer patients receiving IL-2 treat-ment.44 As well as activating the HPA axis, TNF-α increasesbrain tryptophan concentrations and norepinephrine metabo-lism in mice,45 whereas IL-6 increases brain tryptophan andserotonin levels.46 Interleukin-10 enhances CRF and ACTHproduction in hypothalamic and pituitary tissues, respec-tively.47 Granulocyte–macrophage colony-stimulating factorstimulates ACTH and corticosterone production.48

Cytokines also regulate the secretion of non-HPA axishormones. For example, IFN-γ, granulocyte colony-stimulating factor (G-CSF) and GM-CSF stimulate melatoninrelease by the pineal gland.49,50 Potentially, this constitutes yetanother positive feedback loop because melatonin itselfenhances IFN-γ production.24,51 Interferon-γ upregulatesglucocorticoid receptor expression by macrophages,52 sug-gesting that the action of glucocorticoids on immune cellsmay be enhanced at times of immune system activation.

Some cytokines may even cross-react with neuroen-docrine receptors. For example, IL-2 has analgesic effects inboth the central and peripheral nervous systems and this maybe mediated through interaction of the analgesic domain of IL-2 with the opioid receptor.53

Expression of hormones by immune cells

Lymphocytes express receptors for a wide variety of hor-mones, including cortisol, prolactin, GH and melatonin.

Immune cells are also capable themselves of expressingmany hormones. Over 20 different neuroendocrine hormonesand/or mRNA for hormones including ACTH, thyroid-stimulating hormone (TSH), GH, prolactin and CRH areexpressed by lymphocytes and/or monocytes.54 For example,human PBMC express gonadotropin-releasing hormone(GnRH), GnRH receptor, and IL-2 receptor gamma-chainmRNA that are regulated by GnRH in vitro.55 Thymus-expressed glucocorticoids may even have a role in the regu-lation of antigen-specific T-cell development.56

Expression of cytokines by neuroendocrine cells

The hypothalamus and/or anterior pituitary have been shownto express IL-1, IL-6, TGF-β, LIF and other cytokines.57,58

Nervous tissue also expresses IL-2.59 Using a combination ofimmunocytochemical and immunohistological techniques,preformed MIF has been shown to account for approximately0.05% of total protein in the anterior pituitary gland.60 Thiscompares to 0.2% and 0.08%, respectively, for the classicalpituitary hormones ACTH and prolactin. Macrophageinhibitory factor colocalizes in the same population of secretory granules as ACTH and stimulation of cultured pitu-itary cells with CRF results in a dose-dependent release ofMIF.61 The secretion of MIF occurs at lower CRF concentra-tions than those required to induce ACTH secretion. Anteriorpituitary cells also secrete large quantities of MIF when stimulated with LPS, in vitro.61 Interleukin-10 is another cyto-kine produced by pituitary, hypothalamic and neural tissues.47

Initially found in immune cells, IL-18 mRNA is detectable incells of the zona reticularis and the zona fasciculata of theadrenal cortex, where its levels are elevated by acute stress orACTH administration.62

Neuroendocrine innervation of lymphoid organs

Sympathetic postganglionic nerve fibres are present in bothprimary and secondary lymphoid organs. The roles of thesenerves are not well understood. Through innervation of vas-cular smooth muscle within lymphoid organs, one role ofthese nerve fibres may be to control vascularity of lymphoidtissues. Noradrenalin itself has immune activity and itsrelease from sympathetic nerve ends in lymphoid organs mayhave a direct role in immunomodulation. Other factorssecreted by nerve endings that could also have immunomo-dulatory roles include the neuropeptides; substance P, vaso-active intestinal polypeptide, calcitonin-gene-related peptideand neurokinin A. In some cases, histology has shownimmune cells, including mast cells, macrophages or T cells,to be in direct communication with peripheral nerve endings.63

Neuroendocrine immune cross-talk

A good example of neuroendocrine immune cross-talk is therole of prolactin in regulating T-cell cytokine production. Prolactin shares target transcription factors including inter-feron regulatory factor-1 (IRF-1) with IL-2.64 Prolactinreceptors are expressed on T and NK cells and prolactinincreases IL-2-stimulated NK-cell IFN-γ production.64 This is an example of an increasingly recognized phenomenawhereby simultaneous signalling via hormone and cytokine

N Petrovsky352

receptors on T cells results in downstream interaction ofreceptor signalling pathways and results in T-cell behaviourthat may not be predicted on the basis of signalling throughindividual receptors. Given that T cells express over 20neuroendocrine receptors and at least as many cytokinereceptors the level of complexity of intracellular cross-talkmust be immense. The diversity of T-cell behaviour under dif-ferent conditions is likely, therefore, to have its origins in thisreceptor cross-talk involving neuroendocrine and cytokinereceptors. Thus, reductionist experiments examining the roleof individual factors in T-cell subset differentiation may beless important than examination of the overall cytokine andhormonal milieu in vivo at the time of T-cell activation inunderstanding T-cell subset differentiation.

Neuroendocrine regulation of Th1/Th2 balance

Interferon-γ and IL-12 are key regulators of Th1 responses,whereas IL-4 and IL-13 regulate Th2 function. It is unlikely,however, that these cytokines are the primary determinant ofTh1 or Th2 polarization of the immune response. What ismore likely is that the neuroendocrine environment plays acritical role in shaping the immune response. For example,melatonin, DHEAS, adrenalin and adenosine impart a Th1bias, whereas progesterone, glucocorticoids, histamine, nor-adrenalin and 1,25 vitamin D result in a Th2 bias.13,14,17,28,64–69

Given that the levels and ratios of these neuroendocrinefactors are constantly changing, this could have a major rolein determining the subtype of an immune response. One wayof testing this hypothesis would be to look for diurnal vari-ation in immune function. This might be expected if diurnallyregulated neuroendocrine factors were indeed controlling T-cell subset behaviour.

Human diurnal cytokine rhythms

Serum IL-1, IL-6 and soluble IL-2 receptors peak at 1–4 AM

and are low throughout the day with a nadir at 8–10 AM.70–73

Many cytokines, however, cannot normally be detected inhuman plasma or serum. Short-term cultures, ex vivo, confirmthat IFN-γ, IL-10, IL-12 and TNF-α, also exhibit diurnalrhythmicity with night-time or early morning peaks.74,75

Neuroendocrine entrainment of cytokine rhythms

Cortisol, the major circulating human glucocorticoid, is apowerful natural immuno-suppressant. Plasma cortisolexhibits a well-defined diurnal rhythm76 that could be anti-cipated to impose diurnal variation on immune responsive-ness. Therefore, periods of heightened immune reactivitywould be anticipated to coincide with or follow the earlymorning nadir in plasma cortisol. Interferon-γ, IL-12 andTNF-α are inversely correlated with plasma cortisol.74

Manipulation of plasma cortisol within the normal physio-logical range results in reciprocal changes in whole bloodIFN-γ, IL-12, TNF-α, IL-1 and, to a lesser extent, IL-6 and IL-10 production proving that diurnal rhythms of pro-inflammatory cytokine production are indeed negativelyentrained by plasma cortisol.74

Interestingly, human cytokines are inhibited to differingdegrees by physiological levels of plasma cortisol with IFN-γ,

IL-12 and TNF-α being most sensitive, IL-1 intermediate,and IL-6 and IL-10 least sensitive, to inhibition by physio-logical levels of cortisol.74 The sensitivity of mouse cytokinesdiffers from humans in that IFN-γ, IL-1, IL-4 and IL-10 aremost sensitive, and TNF-α, GM-CSF, IL-2 and IL-3 mostresistant, to suppression by dexamethasone.77

Cortisol is not the only neuroendocrine factor that couldentrain diurnal rhythmicity in immune function. Melatonin,GH, prolactin, 17-hydroxyprogesterone and DHEAS alsopossess immunomodulatory action78 and exhibit diurnal secre-tion. Plasma melatonin and androstenedione peak at approxi-mately 3 AM, whereas levels of GH and prolactin peak soonafter the onset of sleep.79 Levels of 17-hydroxyprogesteroneand cortisol both peak at approximately 9 AM. Melatoninstimulates IL-123 and IFN-γ24 production by human macro-phages and mouse splenocytes, respectively, and counteractsthe immunosuppressive effects of glucocorticoids on antiviralresistance and thymic weight in mice.25

There is a significant positive correlation between plasmamelatonin and whole blood IFN-γ and IL-12, but not TNF-α,IL-1 or IL-10 production. Oral melatonin accentuates thenight-time peak of IFN-γ, reduces IL-10, but has no measur-able effect on the diurnal rhythms of IL-12 or TNF-α(N Petrovsky, unpubl. data, 1996). Melatonin therapy(20 mg/day) in patients with solid tumours induces a signifi-cant decline in plasma TNF-α,80 and this is consistent withmelatonin playing a role in regulating cytokine production.Interestingly, another pineal indole, 5-methoxytryptophol,which reaches its highest levels during the light phase of theday and whose circadian secretion is thereby opposite to thatof melatonin, significantly increases serum concentrations ofIL-2, while decreasing serum concentrations of IL-6.81 Inrelation to other hormones that may be involved in regulatingdiurnal cytokine rhythms, a strong negative correlation hasbeen reported between the diurnal rhythm of β-endorphin andplasma IL-1β levels,82 although a direct causal associationhas yet to be shown.

Although there is a positive correlation between wholeblood IFN-γ production and plasma melatonin or androstene-dione and a negative correlation between IFN-γ and plasmacortisol or 17-hydroxyprogesterone, thus far, with the excep-tion of cortisol and melatonin, it is not possible to saywhether these hormones independently regulate cytokineexpression in vivo. It is interesting, however, to note that thediurnal rhythms of cortisol and 17-hydroxyprogesterone, hor-mones that impart Th2 bias, peak synchronously at approxi-mately 9 A M and, likewise, the rhythms of melatonin andandrostenedione, hormones associated with Th1 bias, peaksynchronously between 3 and 5 A M .

Neuroendocrine regulation of Th1/Th2 diurnal balance

Although the role of IL-10 in human immune patho-physiology is not as well defined, the IFN-γ to IL-10 ratio hasbeen found to be useful in determining the pro- or anti-inflammatory bias of T-cell culture supernatant.83 Using theratio of IFN-γ to IL-10 production in stimulated whole bloodas an index of type 1/type 2 immune balance we showed thatthe IFN-γ/IL-10 ratio exhibits a diurnal rhythm peaking at4 A M and with a nadir at 3 PM.75 The ratio is negatively correlated with plasma cortisol and its peak is synchronous

Neuroendocrine–immune interactions 353

with the cortisol nadir, and cortisone administration markedlyreduced the ratio consistent with a causal relationship. Thereis a strong positive correlation between plasma melatonin and the IFN-γ/IL10 ratio and the melatonin administrationphase advanced the peak of the IFN-γ/IL-10 ratio by 3 h (N Petrovsky, unpubl. data, 1996). As IFN-γ and IL-10 aremarkers of cellular and humoral immunity, respectively, theabove findings suggest there is a bias toward cellular immu-nity during the night and early morning when the IFN-γ/IL-10 ratio is high and conversely a relative bias towardshumoral immunity during the day.

As Th1 and Th2 responses exhibit reciprocal antagonism,alternating periods of Th1 and Th2 bias may help facilitatethe parallel development of otherwise mutually antagonisticarms of the immune response. As the primary immuneresponse matures, one or other response may preferentiallyexpand and ultimately override this alternating diurnallyimposed bias, thereby resulting in either Th1 or Th2 polar-ization. Diurnal variation of Th1/Th2 balance may havearisen in response to evolutionary pressures as Th1 responsesare associated with inflammation, swelling, pain, immobilityand malaise. It would be advantageous, therefore, to restrictTh1 responses to inactive ‘healing’ periods (night-time inhumans) and not to active periods when maximum mobilityis required for hunting, gathering and ‘fight or flight’responses. It certainly makes sense, given the siting of thebiological clock in the suprachiasmic nucleus, and the abilityof the brain to integrate other information such as the overalllevel of stress, that the neuroendocrine system should entrainthe immune response in such situations.

Neuroendocrine-entrained cytokine rhythms anddisease

The symptoms of immuno-inflammatory disorders, forexample rheumatoid arthritis (RA) or asthma, commonlyexhibit diurnal rhythmicity. Joint inflammation in RA is at its most severe in the early morning84 and asthma exacer-bations commonly occur during the night.85,86 Impaired func-tion of the HPA axis has been implicated in RA,87 andnocturnal exacerbations of asthma are associated with theearly morning nadir in plasma cortisol.88 Night-time or earlymorning exacerbations of inflammatory disorders are likelyto reflect diurnally increased production of pro-inflammatorycytokines. Consistent with this hypothesis, patients with RAhave significant diurnal variation of IL-6 with peak values inthe morning and low values in the afternoon.89,90 Similarly,bronchoalveolar lavage fluid concentrations of IL-1β are significantly greater at 4 A M than at 4 P M in asthmatics with nocturnal airflow obstruction.91

Significance of neuroendocrine immune cross-talk

The neuroendocrine and immune systems both act to protectthe internal homeostasis of the organism and it is not sur-prising, therefore, that they should be so closely intertwined.Infections are regarded by the neuroendocrine system asstressors, just like other stressors such as blood loss or emo-tional distress. The function of the neuroendocrine system inthe face of stresses, such as infection, is to protect the homeo-stasis of the body. In the case of infection this may involve

working for or against the immune system. Activation of theimmune system poses potential dangers not just to the inva-ding microorganism, but also to the integrity of the host, foran overly vigorous response (e.g. toxic shock syndrome), maykill the host in the process of controlling an infection. Theneuroendocrine system must, therefore, constantly monitorand if necessary regulate the activities of the immune systemto ensure the integrity of the host. Conversely, the immunesystem needs the neuroendocrine system to help determinethe context of a perceived threat and how best to respond. Abreakdown in this communication may be responsible forproblems such as autoimmunity, chronic infection or septicshock. This is consistent with evidence that in animalmodels, which are prone to autoimmunity such as the Bio-breeding (BB)-rat or obese-strain chicken, this susceptibilitycan be traced back to a neuroendocrine defect, most com-monly in the HPA axis.

The neuroendocrine and immune systems have evolved,therefore, a complex system of cross-talk whereby they sharean extensive range of common messenger molecules andreceptors and can monitor and regulate each other’s activities.The complex interaction of these systems is exemplified bythe role of neuroendocrine hormones in the regulation ofdiurnal rhythms of immune function and, in particular,diurnal variation in Th1/Th2 balance as previously described.The close relationship of the neuroendocrine and immunesystems suggests in fact that they have evolved into a singlehigher-order entity concerned with maintaining the integrityand safety of the body against both internal and externalthreats.

Acknowledgements

This work was supported by a grant from the Canberra Hospital Salaried Specialists Private Practice Fund.

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