Special Feature

Immunology and Cell Biology (2001) 79, 350–357; doi:10.1046/j.1440-1711.2001.01029.x

Towards a unified model of neuroendocrine–immune interaction

Nikolai Petrovsky1

1Autoimmunity Research Unit, Canberra Clinical School, University of Sydney and Division of Science and Design, University of Canberra, Canberra, Australian Capital Territory, Australia

Correspondence: Assoc. Prof. N Petrovsky, NHSC Autoimmunity Research Unit, The Canberra Hospital, PO Box 11, Woden, ACT 2606, Australia. Email: nikolai.petrovsky@anu.edu.au

Received 4 May 2001; Accepted 4 May 2001.

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Abstract

Although the neuroendocrine system has immunomodulating potential, studies examining the relationship between stress, immunity and infection have, until recently, largely been the preserve of behavioural psychologists. Over the last decade, however, immunologists have begun to increasingly appreciate that neuroendocrine–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 molecules variously called neurotransmitters, cytokines or hormones. Their classification as neurotransmitters, cytokines or hormones is more serendipity than a true reflection of their sphere of influence. Rather than these systems being discrete entities we would propose that they constitute, in reality, a single higher-order entity. This paper reviews current knowledge of neuroendocrine–immune interaction and uses the example of T-cell subset differentiation to show 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.

Keywords:

cytokine, immune, neuroendocrine, regulation, T-cell subsets

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Hormonal regulation of immune function

To give an idea of the incredible extent to which the neuroendocrine system is important in the regulation of immune function, Table 1 lists just some of the known neuroendocrine factors 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 adrenocorticotrophic hormone (ACTH) and this in turn stimulates glucocorticoid secretion by the adrenals. Glucocorticoid secretion is regulated by negative feedback, cortisol inhibiting the secretion of both CRF and ACTH. The glucocorticoids are among the best-characterized hormones, possessing powerful and far-reaching immunoregulatory activity. Glucocorticoids exert powerful anti-inflammatory actions, inhibiting inflammatory mediators including cytokines, phospholipid products, proteases and oxygen metabolites.1 They downregulate cytokine expression by binding to, and activating, negative regulatory elements in the promoters of cytokine genes,2, 3, 4 and by inducing production of IkappaB-alpha, a protein that binds and neutralizes the cytokine transcription factor nuclear factor-kappaB (NF-kappaB).5 Cytokines downregulated by glucocorticoids include IL-1,6 IL-2 and IFN-gamma,2 IL-3, GM-CSF and TNF-alpha,7 IL-4,8 IL-63 and IL-8.4 Interestingly, glucocorticoids induce release of macrophage inhibitory factor (MIF), an inflammatory 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 immunity, glucocorticoids enhance immunoglobulin production.11 Furthermore, at glucocorticoid levels that inhibit IL-2 production, IL4 production is increased.12 Glucocorticoids bias in favour of the development of T cells that produce Th2 cytokines.13 T cells primed in the presence of low concentrations of glucocorticoids preferentially express IL-10 at levels up to fivefold higher than in the absence of beclamethasone.14 Glucocorticoids also increase TGF-beta mRNA expression by both unstimulated and PHA-stimulated T cells.15 The propensity of glucocorticoids to increase production of IL-4, IL-10 and TGF-beta is consistent with their imparting a selective bias towards 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 role in 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 monocytes and ACTH suppresses IFN-gamma production by human lymphocytes.17 Growth hormone (GH) activates human macrophages and primes monocytes for enhanced H2O2 release.18 When given to hypopituitary animals, growth hormone augments antibody synthesis and skin graft rejection.19 Similarly, prolactin enhances macrophage function. Reduced prolactin release in response to bromocryptine administration is associated with suppression of macrophage tumouricidal activity, impaired IFN-gamma production and depressed T-cell proliferation.20 These defects are all reversed by administration of exogenous prolactin.20 Other pituitary hormones with immunoregulatory activity include follicle-stimulating hormone and luteinizing hormone21 and thyroid-stimulating hormone.22

It is not only hormones that originate in the HPA axis that have immunoregulatory activity. Melatonin as secreted by the pineal gland sensitizes monocytes to LPS activation and enhances IL-123 and IFN-gamma production.24 Melatonin, administered in vivo, antagonizes the immunosuppressive effects of cortisol and prevents cortisone-induced thymic atrophy.25 Melatonin also regulates IL-12 and nitric oxide production by primary cultures of rheumatoid synovial macrophages and the THP-1 monocytic cell line, suggesting a possible role in rheumatoid arthritis.26 Other hormones with immunoregulatory activity (summarized in Table 1) include dehydroepiandrosterone sulfate (DHEAS),27, 28, 29 beta-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 cytokine receptor gene expression. For example, 17beta-oestradiol markedly increases activity of the IFN-gamma gene promoter in lymphoid cells.36 Similarly, progesterone induces transient IL-4 gene expression in established TH1 clones,28 while glucocorticoids upregulate immune cell expression of receptors for IL-1, IL-2, IL-6 and IFN-gamma.37

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Cytokine regulation of neuroendocrine function

In keeping with the bidirectional nature of the neuroendocrine and immune pathways, cytokines also influence neuroendocrine function. This was highlighted by the early finding that corticosterone levels are increased several fold during the primary immune response of rats to sheep red blood cells. Immune influences on neuroendocrine function are now known to be principally mediated by cytokines, receptors for which are widely expressed throughout the neuroendocrine system.

The first cytokines shown to have neuroendocrine effects were the interferons, administration of which increases steroidogenesis. Subsequently, IL-1, IL-2 or IL-6, IFN-beta, IFN-gamma, leukaemia inhibitory factor (LIF) and TNF-alpha have been shown to elevate plasma ACTH and glucocorticoid levels in both laboratory animals and humans.38, 39, 40, 41 IL-1, -2 and -6 and TNF-alpha all directly stimulate cortisol secretion by adrenal cells in culture and IL-1 and -6 stimulate cultured pituitary cells to produce ACTH and beta-endorphin.42 The glucocorticoid-inducing effect of IL-1, in vivo, is abrogated by the administration of CRH antagonists. This suggests that the principal pathway by which cytokines induce glucocorticoid secretion is via stimulation of hypothalamic CRH secretion rather than via direct stimulation of adrenal glucocorticoid production. Interestingly, IL-2 is the most potent secretagogue for ACTH currently identified and is more active on a molar basis than CRH, the classical regulator of ACTH secretion.43 This explains the elevation of cortisol levels observed in cancer patients receiving IL-2 treatment.44 As well as activating the HPA axis, TNF-alpha increases brain tryptophan concentrations and norepinephrine metabolism in mice,45 whereas IL-6 increases brain tryptophan and serotonin levels.46 Interleukin-10 enhances CRF and ACTH production in hypothalamic and pituitary tissues, respectively.47 Granulocyte–macrophage colony-stimulating factor stimulates ACTH and corticosterone production.48

Cytokines also regulate the secretion of non-HPA axis hormones. For example, IFN-gamma, granulocyte colony- stimulating factor (G-CSF) and GM-CSF stimulate melatonin release by the pineal gland.49, 50 Potentially, this constitutes yet another positive feedback loop because melatonin itself enhances IFN-gamma production.24, 51 Interferon-gamma upregulates glucocorticoid receptor expression by macrophages,52 suggesting that the action of glucocorticoids on immune cells may be enhanced at times of immune system activation.

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

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Expression of hormones by immune cells

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

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Expression of cytokines by neuroendocrine cells

The hypothalamus and/or anterior pituitary have been shown to express IL-1, IL-6, TGF-beta, LIF and other cytokines.57, 58 Nervous tissue also expresses IL-2.59 Using a combination of immunocytochemical and immunohistological techniques, preformed MIF has been shown to account for approximately 0.05% of total protein in the anterior pituitary gland.60 This compares to 0.2% and 0.08%, respectively, for the classical pituitary hormones ACTH and prolactin. Macrophage inhibitory factor colocalizes in the same population of secretory granules as ACTH and stimulation of cultured pituitary cells with CRF results in a dose-dependent release of MIF.61 The secretion of MIF occurs at lower CRF concentrations than those required to induce ACTH secretion. Anterior pituitary cells also secrete large quantities of MIF when stimulated with LPS, in vitro.61 Interleukin-10 is another cytokine produced by pituitary, hypothalamic and neural tissues.47 Initially found in immune cells, IL-18 mRNA is detectable in cells of the zona reticularis and the zona fasciculata of the adrenal cortex, where its levels are elevated by acute stress or ACTH administration.62

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Neuroendocrine innervation of lymphoid organs

Sympathetic postganglionic nerve fibres are present in both primary and secondary lymphoid organs. The roles of these nerves are not well understood. Through innervation of vascular smooth muscle within lymphoid organs, one role of these nerve fibres may be to control vascularity of lymphoid tissues. Noradrenalin itself has immune activity and its release from sympathetic nerve ends in lymphoid organs may have a direct role in immunomodulation. Other factors secreted by nerve endings that could also have immunomodulatory roles include the neuropeptides; substance P, vasoactive intestinal polypeptide, calcitonin-gene-related peptide and neurokinin A. In some cases, histology has shown immune cells, including mast cells, macrophages or T cells, to be in direct communication with peripheral nerve endings.63

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Neuroendocrine immune cross-talk

A good example of neuroendocrine immune cross-talk is the role of prolactin in regulating T-cell cytokine production. Prolactin shares target transcription factors including interferon regulatory factor-1 (IRF-1) with IL-2.64 Prolactin receptors are expressed on T and NK cells and prolactin increases IL-2-stimulated NK-cell IFN-gamma production.64 This is an example of an increasingly recognized phenomena whereby simultaneous signalling via hormone and cytokine receptors on T cells results in downstream interaction of receptor signalling pathways and results in T-cell behaviour that may not be predicted on the basis of signalling through individual receptors. Given that T cells express over 20 neuroendocrine receptors and at least as many cytokine receptors the level of complexity of intracellular cross-talk must be immense. The diversity of T-cell behaviour under different conditions is likely, therefore, to have its origins in this receptor cross-talk involving neuroendocrine and cytokine receptors. Thus, reductionist experiments examining the role of individual factors in T-cell subset differentiation may be less important than examination of the overall cytokine and hormonal milieu in vivo at the time of T-cell activation in understanding T-cell subset differentiation.

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Neuroendocrine regulation of Th1/Th2 balance

Interferon-gamma 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 of Th1 or Th2 polarization of the immune response. What is more likely is that the neuroendocrine environment plays a critical role in shaping the immune response. For example, melatonin, DHEAS, adrenalin and adenosine impart a Th1 bias, whereas progesterone, glucocorticoids, histamine, noradrenalin and 1,25 vitamin D result in a Th2 bias.13, 14, 17, 28, 64, 65, 66, 67, 68, 69 Given that the levels and ratios of these neuroendocrine factors are constantly changing, this could have a major role in determining the subtype of an immune response. One way of testing this hypothesis would be to look for diurnal variation in immune function. This might be expected if diurnally regulated neuroendocrine factors were indeed controlling T-cell subset behaviour.

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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, 71, 72, 73 Many cytokines, however, cannot normally be detected in human plasma or serum. Short-term cultures, ex vivo, confirm that IFN-gamma, IL-10, IL-12 and TNF-alpha, also exhibit diurnal rhythmicity with night-time or early morning peaks.74, 75

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Neuroendocrine entrainment of cytokine rhythms

Cortisol, the major circulating human glucocorticoid, is a powerful natural immuno-suppressant. Plasma cortisol exhibits a well-defined diurnal rhythm76 that could be anticipated to impose diurnal variation on immune responsiveness. Therefore, periods of heightened immune reactivity would be anticipated to coincide with or follow the early morning nadir in plasma cortisol. Interferon-gamma, IL-12 and TNF-alpha are inversely correlated with plasma cortisol.74 Manipulation of plasma cortisol within the normal physiological range results in reciprocal changes in whole blood IFN-gamma, IL-12, TNF-alpha, IL-1 and, to a lesser extent, IL-6 and IL-10 production proving that diurnal rhythms of pro-inflammatory cytokine production are indeed negatively entrained by plasma cortisol.74

Interestingly, human cytokines are inhibited to differing degrees by physiological levels of plasma cortisol with IFN-gamma, IL-12 and TNF-alpha being most sensitive, IL-1 intermediate, and IL-6 and IL-10 least sensitive, to inhibition by physiological levels of cortisol.74 The sensitivity of mouse cytokines differs from humans in that IFN-gamma, IL-1, IL-4 and IL-10 are most sensitive, and TNF-alpha, GM-CSF, IL-2 and IL-3 most resistant, to suppression by dexamethasone.77

Cortisol is not the only neuroendocrine factor that could entrain diurnal rhythmicity in immune function. Melatonin, GH, prolactin, 17-hydroxyprogesterone and DHEAS also possess immunomodulatory action78 and exhibit diurnal secretion. Plasma melatonin and androstenedione peak at approximately 3 AM, whereas levels of GH and prolactin peak soon after the onset of sleep.79 Levels of 17-hydroxyprogesterone and cortisol both peak at approximately 9 AM. Melatonin stimulates IL-123 and IFN-gamma24 production by human macrophages and mouse splenocytes, respectively, and counteracts the immunosuppressive effects of glucocorticoids on antiviral resistance and thymic weight in mice.25

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

Although there is a positive correlation between whole blood IFN-gamma production and plasma melatonin or androstenedione and a negative correlation between IFN-gamma and plasma cortisol or 17-hydroxyprogesterone, thus far, with the exception of cortisol and melatonin, it is not possible to say whether these hormones independently regulate cytokine expression in vivo. It is interesting, however, to note that the diurnal rhythms of cortisol and 17-hydroxyprogesterone, hormones that impart Th2 bias, peak synchronously at approximately 9 AM and, likewise, the rhythms of melatonin and androstenedione, hormones associated with Th1 bias, peak synchronously between 3 and 5 AM.

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Neuroendocrine regulation of Th1/Th2 diurnal balance

Although the role of IL-10 in human immune pathophysiology is not as well defined, the IFN-gamma to IL-10 ratio has been found to be useful in determining the pro- or anti-inflammatory bias of T-cell culture supernatant.83 Using the ratio of IFN-gamma to IL-10 production in stimulated whole blood as an index of type 1/type 2 immune balance we showed that the IFN-gamma/IL-10 ratio exhibits a diurnal rhythm peaking at 4 AM and with a nadir at 3 PM.75 The ratio is negatively correlated with plasma cortisol and its peak is synchronous with the cortisol nadir, and cortisone administration markedly reduced the ratio consistent with a causal relationship. There is a strong positive correlation between plasma melatonin and the IFN-gamma/IL10 ratio and the melatonin administration phase advanced the peak of the IFN-gamma/IL-10 ratio by 3 h (N Petrovsky, unpubl. data, 1996). As IFN-gamma and IL-10 are markers of cellular and humoral immunity, respectively, the above findings suggest there is a bias toward cellular immunity during the night and early morning when the IFN-gamma/ IL-10 ratio is high and conversely a relative bias towards humoral immunity during the day.

As Th1 and Th2 responses exhibit reciprocal antagonism, alternating periods of Th1 and Th2 bias may help facilitate the parallel development of otherwise mutually antagonistic arms of the immune response. As the primary immune response matures, one or other response may preferentially expand and ultimately override this alternating diurnally imposed bias, thereby resulting in either Th1 or Th2 polarization. Diurnal variation of Th1/Th2 balance may have arisen in response to evolutionary pressures as Th1 responses are associated with inflammation, swelling, pain, immobility and malaise. It would be advantageous, therefore, to restrict Th1 responses to inactive 'healing' periods (night-time in humans) and not to active periods when maximum mobility is required for hunting, gathering and 'fight or flight' responses. It certainly makes sense, given the siting of the biological clock in the suprachiasmic nucleus, and the ability of the brain to integrate other information such as the overall level of stress, that the neuroendocrine system should entrain the immune response in such situations.

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Neuroendocrine-entrained cytokine rhythms and disease

The symptoms of immuno-inflammatory disorders, for example rheumatoid arthritis (RA) or asthma, commonly exhibit diurnal rhythmicity. Joint inflammation in RA is at its most severe in the early morning84 and asthma exacerbations commonly occur during the night.85, 86 Impaired function of the HPA axis has been implicated in RA,87 and nocturnal exacerbations of asthma are associated with the early morning nadir in plasma cortisol.88 Night-time or early morning exacerbations of inflammatory disorders are likely to reflect diurnally increased production of pro-inflammatory cytokines. Consistent with this hypothesis, patients with RA have significant diurnal variation of IL-6 with peak values in the morning and low values in the afternoon.89, 90 Similarly, bronchoalveolar lavage fluid concentrations of IL-1beta are significantly greater at 4 AM than at 4 PM in asthmatics with nocturnal airflow obstruction.91

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Significance of neuroendocrine immune cross-talk

The neuroendocrine and immune systems both act to protect the internal homeostasis of the organism and it is not surprising, therefore, that they should be so closely intertwined. Infections are regarded by the neuroendocrine system as stressors, just like other stressors such as blood loss or emotional distress. The function of the neuroendocrine system in the face of stresses, such as infection, is to protect the homeostasis of the body. In the case of infection this may involve working for or against the immune system. Activation of the immune system poses potential dangers not just to the invading microorganism, but also to the integrity of the host, for an overly vigorous response (e.g. toxic shock syndrome), may kill the host in the process of controlling an infection. The neuroendocrine system must, therefore, constantly monitor and if necessary regulate the activities of the immune system to ensure the integrity of the host. Conversely, the immune system needs the neuroendocrine system to help determine the context of a perceived threat and how best to respond. A breakdown in this communication may be responsible for problems such as autoimmunity, chronic infection or septic shock. This is consistent with evidence that in animal models, which are prone to autoimmunity such as the Bio-breeding (BB)-rat or obese-strain chicken, this susceptibility can be traced back to a neuroendocrine defect, most commonly in the HPA axis.

The neuroendocrine and immune systems have evolved, therefore, a complex system of cross-talk whereby they share an extensive range of common messenger molecules and receptors and can monitor and regulate each other's activities. The complex interaction of these systems is exemplified by the role of neuroendocrine hormones in the regulation of diurnal rhythms of immune function and, in particular, diurnal variation in Th1/Th2 balance as previously described. The close relationship of the neuroendocrine and immune systems suggests in fact that they have evolved into a single higher-order entity concerned with maintaining the integrity and safety of the body against both internal and external threats.

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Acknowledgements

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