Immune-Neuro-Endocrine Interactions: Facts and

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0163-769X/96/$03.00/0 Endocrine Reviews Copyright © 1996 by The Endocrine Society

Vol. 17, No. 1 Printed in U.S.A.

Immune-Neuro-Endocrine Interactions: Facts and Hypotheses HUGO OSCAR BESEDOVSKY AND ADRIANA DEL REY Division of Immunophysiology, Institute of Physiology, Medical Faculty, Deutschhausstrafie 2, D-35037 Marburg, Germany

I. Introduction

I. Introduction II. Reciprocal Effects Between Immune and Neuro-Endocrine Mechanisms A. Receptors for cytokines, hormones, neurotransmitters, and neuropeptides in immune, endocrine, and neural cells 1. Receptors for hormones, neurotransmitters, and neuropeptides in immune cells 2. Receptors for immune cytokines in endocrine glands 3. Receptors for immune cytokines in the nervous system B. Immune and neuro-endocrine products coexist in lymphoid, endocrine, and neural tissues 1. Neuro-endocrine agents in lymphoid organs 2. Immune cytokines in endocrine and nervous systems C. Hormones, neurotransmitters, and neuropeptides can affect the immune system 1. Endocrine effects on the immune system 2. Neural effects on the immune system 3. Immune mechanisms that can be affected by neuro-endocrine agents D. Immune cell products can affect neuro-endocrine mechanisms 1. Effects of immune-derived products on endocrine mechanisms 2. Effects of immune-derived products on the nervous system 3. Metabolic effects of cytokines III. Immune-Neuro-Endocrine Circuits A. Long loop immune-neuro-endocrine circuits B. Immune-neuro-endocrine circuits operating at local levels C. Relevance of immune-neuro-endocrine circuits for immunoregulation IV. Homeostatic and Antihomeostatic Functions of the Immune System: Contribution to Natural Selection V. Outlook A. The immune system as a diffuse, sensorial receptor organ B. Is that all?

T

HE existence of mechanisms that provide immunity to an infective agent was inferred from empirical observations obtained through the ingenuity and deductive capacity of early investigators. The first procedures for vaccinations and serotherapy resulted from these observations. The implementation of these procedures, probably the most important contribution of immunology to medical science, was, at first, based on a very rudimentary knowledge of the immune system. During the first half of the 20th century, this rather primitive knowledge coincided with evidence showing that the endocrine and nervous systems integrate and regulate different bodily functions. Therefore, based on some supportive data, it was considered that immune mechanisms may also be influenced by these systems. However, at the beginning of the second half of the 20th century, most efforts were directed at understanding the molecular and cellular basis of the immune response and the mechanisms of acquisition of immunological diversity and self-tolerance. The product of these studies is formidable. As a result, we know the structure of the main molecules (e.g. antibodies, T cell receptors) that allow recognition of antigens from inside and outside the organism, as well as the types and subtypes of cells that participate in an immune response. In addition, the molecular and genetic basis of the differentiation and diversification of immunological cells is largely understood. Furthermore, our knowledge of the biochemical and molecular basis of immune cell activation and how these cells interact and receive information from antigen-presenting cells has been clarified to a great extent. The existence of autoregulatory mechanisms that can control the immune response has also been established. In contrast, much less is known about how immunological cells and their products interact with other bodily systems, and about the consequences of such interactions for mechanisms intrinsic and extrinsic to the immune system. Thus, the understanding of the organization of the immune system itself has raised essential questions concerning its physiological functioning within the whole organism. The need to provide answers to these questions is becoming increasingly important, and many laboratories are now focused on understanding the functional and molecular basis of interactions between the immune system and integrative neuro-endocrine mechanisms. As we shall discuss later, interactions between the immune, endocrine, and nervous systems are necessarily complex since each of these systems is intrinsically complex.

Address reprint requests to: Hugo O. Besedovsky, M. D., Division of Immunophysiology, Institute of Physiology, Medical Faculty, Deutschhausstraj3e 2, D-35037 Marburg, Germany. This work was supported by the Volkswagen Stiftung.

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IMMUNE-NEURO-ENDOCRINE INTERACTIONS

Furthermore, the amount of information that is now available is enormous, and, in some instances, contradictory or ^ difficult to interpret. Therefore, this article will not be an exhaustive review of all the contributions from the multiple laboratories engaged in this field of research. Instead, it will provide an analysis of the available information within a defined conceptual framework, which, even if it turns out to be wrong in certain aspects, might serve to promote further . research. The main focus of this article will be on functional interactions between immune, neural, and endocrine cells and their possible relevance to physiological and certain pathological processes. These interactions occur at so many levels that it is necessary to establish some priorities and restrictions for the following discussion. We shall particularly high* light those studies of the effects of the products of immune cells on neuro-endocrine functions since the existence of afferent pathways from the immune system to mechanisms under central nervous system (CNS) control is now being intensively investigated. Certain aspects that will either be absent or only briefly discussed include psychosocial influ• ences on immunity, neuroimmunological brain diseases, effects of immune cell products on behavior, thermoregulation and sleep, and endocrine diseases caused by the immune system. Molecular and subcellular processes underlying immune-neuro-endocrine interactions will not be discussed in detail, unless it is necessary for understanding the biological relevance of such interactions. We shall often refer to cytokines as immune-derived prod*• ucts. However, at present, the term cytokine is widely used to define polypeptidic factors released by practically any type of cells. More than 50 cytokines have been described and the majority have been cloned. Most of them have pleiotropic effects, and some act together synergistically or are capable of inducing or inhibiting the production of other cytokines. »• Many of these factors are produced by immunological cells. The immune-derived cytokines mentioned in this review are those that can be considered as mediators of immune-neuroendocrine interactions because they exert some neuro-endocrine effect or their receptors are present in neuro-endocrine tissues. These cytokines are listed in Table 1, together with v their currently used abbreviation. Their main immunological actions are also briefly summarized.

II. Reciprocal Effects Between Immune and NeuroEndocrine Mechanisms As schematically represented in Fig. 1, the evidence that immune and neuro-endocrine mechanisms can affect each other has been classified as follows: A) Immune, endocrine, or neural cells can express receptors for cytokines, hormones, neurotransmitters, and neuropeptides; B) Immune and neuro-endocrine products coexist in lymphoid, endocrine, and neural tissue; C) Endocrine and neural mediators can affect the immune system; and D) Immune mediators can affect endocrine and neural structures.

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A. Receptors for cytokines, hormones, neurotransmitters, and neuropeptides in immune, endocrine, and neural cells Reciprocal expression of receptors for products of the nervous and endocrine system, as well as for the immune system, constitute the basis of immune-neuro-endocrine interactions. The presence of receptors for hormones, neurotransmitters, and neuropeptides on immunological cells has been clearly established, and only a few classic works will be mentioned below. However, more recent studies on the presence of receptors for immune-derived messengers on endocrine and neural cells will be reviewed in more detail. 1. Receptors for hormones, neurotransmitters, and neuropeptides

in immune cells. Immune cells can bind different hormones, neurotransmitters, and neuropeptides. For example, receptors for corticosteroids (1,2), insulin (3,4), PRL (5,6), GH (7), estradiol (8), testosterone (9), j3-adrenergic agents (10-14), acetylcholine (15,16), endorphins (17), enkephalins (18), substance P (SP), somatostatin (SOM), and vasointestinal peptide (VIP) (19-21) have been demonstrated in lymphoid or accessory cells. There is still some controversy regarding the presence or the number of certain of these receptors on immunological cells. However, for the purpose of this review, we consider it more important to discuss two aspects that are relevant for the final effect of neuro-endocrine agents on immune cells. First, receptors for neuro-endocrine ligands are not equally expressed on all types of immune cells. For example, B lymphocytes express more j3-adrenergic receptors than T lymphocytes, while CD8+ lymphocytes (cy to toxic T cells) express fewer receptors than CD4+ cells (helper T cells) (13). This indicates that signals mediated by hormones, neurotransmitters, and neuropeptides can preferentially target, and therefore influence, different types of immune responses. Second, the number or the activity of receptors for a given neuro-endocrine agent may change during the activation of the cell. For example, resting lymphocytes have no detectable receptors for insulin, but they appear after stimulation with mitogens or allogeneic antigens (3, 4). After stimulation of quiescent cytotoxic T lymphocytes by interleukin-2 (IL-2), there is an increase in j3-adrenergic receptor activity (22). The number of muscarinic receptors on human leukocytes and rat T lymphocytes also increases when these cells are activated by mitogens and allogeneic antigens or during skin graft rejection (23). Thus, it is expected that signals mediated by these hormones or neurotransmitters will be predominantly perceived by cells that have been activated by an antigen. In summary, the presence of receptors for hormones, neurotransmitters, and neuropeptides on immune cells is an absolute requirement for neuro-endocrine agents to exert an effect. However, as clearly established for glucocorticoids (24), the magnitude of the effect of a given ligand does not necessarily correlate with the number of receptors present on the target cell. Thus, the identification of receptors should be taken only as an indication that immune cells can perceive and respond to messengers present in their natural environment. As will be discussed later, several other factors, such as the different degree of sensitivity of the various steps of

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Vol. 17, No. 1

TABLE 1. Cytokines that can mediate immune-neuro-endocrine interactions Abbreviation

Name

Major immune action

IL-la, IL-1/3

Interleukin-1 a; Interleukin-1/3

Differentiation and function of cells involved in inflammatory and immune responses; T T helper cells to produce and secret IL-2 and the expression of IL-2 receptors; f B cell proliferation and production of Ig, f proliferation and activation of NK cells

IL-lra

Interleukin-1 receptor antagonist

I IL-1 activities

IL-2 IL-3

Interleukin-2 Interleukin-3

1 T cell proliferation and differentiation, f NK activity, promotes proliferation of B cells and Ig secretion synergizes with specific factors to stimulate production and differentiation of macrophages (and other blood cells)

IL-4

Interleukin-4

Induces differentiation into T helper cells, proliferation and differentiation of B cells, diverse effects on T cells and monocytes

IL-6

Interleukin-6

Induces growth and differentiation of T cells and B cells, activates hematopoietic progenitor cells

IL-8 IL-12

Interleukin-8 Interleukin-12

Induces chemotactic activity for T cells . Induces differentiation of T helper cells, f growth and activity of T and NK cells

IFN 7

Interferon-y

TNFa

Tumor necrosis factor-a

TGF/3

Transforming growth factor-j3

M-CSF

Macrophage-Colony stimulating factor

I Macrophage activity, regulates specific immune responses Wide immunological effects through induction of other growth factors and cytokines; immunostimulant and mediator of inflammatory response i Growth of many cells, NK activity and T and B cell proliferation; with IL-4 f IgA secretion I Various functions of monocytes and macrophages, promotes growth and development of macrophage colonies

G-CSF GM-CSF

Granulocyte-colony stimulating Granulocyte and macrophage co stimulating factor

I Production of neutrophil and macrophage colonies Promotes growth and differentiation of multipotential progenitor cells, f all cells in the granulocyte, macrophage and eosinophil lineage

SCF

Stem cell factor

Synergizes with various growth factors to f myeloid, erythroid and lymphoid progenitors

The cytokines listed above are produced, although not exclusively, by immunological cells. Only those that, at present, can be considered as mediators of immune-neuro-endocrine interactions because they exert some neuro-endocrine effect or their receptors are present in neuro-endocrine tissues, are included. NK, Natural killer cells; Ig, immunoglobulins; f » stimulate; | , inhibit.

an immune response and the presence of other agents, will influence the final effect of a given ligand. 2. Receptors for immune cytokines in endocrine glands. Comple-

mentary to the studies mentioned above is the identification of receptors for immune-derived products in endocrine glands. These studies are, in general, more recent than those mentioned in the previous section. Although valuable evidence showing the existence of receptors for cytokines on endocrine tissue has been obtained from normal and tumor cell lines, we have chosen studies using normal tissues to illustrate this point. A summary of several of the reports available is given in Table 2, where receptors for interleukins on the pituitary, adrenal, thyroid, pancreas, testis, and ovary are mentioned with the corresponding bibliographic reference (25-39). The table does not indicate whether the methodology used in a given report has resulted in the characterization of a receptor or on the identification of a specific binding site.

As can be seen in Table 2, most reports deal with receptors for IL-1. As a whole, receptors for IL-la and j3, or the corresponding messenger RNA (mRNA), have been identified in rat and mouse pituitary, mainly located in the adenohypophysis. Receptors or binding sites for IL-6 and IL-2 have also been found in the pituitary. IL-1 receptors have not been found in the adrenals (28, 40), although a recent report suggests that they might be present in bovine adrenal medullary cells (41). There are a few reports showing that IL-1 receptors, or the corresponding mRNA, are also present on thyroid cells, in the endocrine pancreas, and in certain regions or specific cells of the ovary and of the testis. 3. Receptors for immune cytokines in the nervous system. After the

finding that exogenous administration of certain cytokines could induce pronounced endocrine changes known to be under neural control (for references see Section D), a large number of reports became available showing that receptors for some of these cytokines can, in fact, be demonstrated in

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IMMUNE-NEURO-ENDOCRINE INTERACTIONS

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Immune and neuro-endocrlne mechanisms can affect each other

Immuno orgon/llaauo

1CYH NTNP

Endocrine gland

FIG. 1. Schematic representation of how immune and neuro-endocrine mechanisms can affect each other: A, Immune, endocrine, or neural cells can express receptors for cytokines, hormones, neurotransmitters, and neuropeptides. B, Immune and neuro-endocrine products coexist in lymphoid, endocrine, and neural tissue. C, Effects of neuro-endocrine agents on immune mechanisms. D, Effects of immune-derived products on neuro-endocrine mechanisms. CY, cytokine; H, hormone; NT, neurotransmitter; NP, neuropeptide.

0. EFFECTS OF IMMUNE-DERIVED PRODUCTS

C. EFFECTS OF NEURO-€NDOCRINE AGENTS

tntarmadiata matabollsm Signal trantductlon Selection Radrculation

Traffic Cytokln** Call interactions Anllgan praaantatlon Effactor ntachaniBins Autoragulatory procatMa

Naurotranamillar Nauropaplide Endocrina Gland

Naurotrantmlllara Nauropaplldaa Nauronal activity Nauronal growth, diftarantlatlon and rapair Thannoragutatlon Food inlaka Slaap Bahavlor

the CNS. Different techniques such as autoradiography, immunoautoradiography, in situ histochemistry, and in situ hybridization histochemistry (at times combined with reverse transcriptase-polymerase chain reaction), have been used. As a whole, the existing evidence indicates the presence in the brain of receptors, or of the corresponding mRNA, for IL-1 a and j3, IL-2, IL-4, IL-6, tumor necrosis factor-a (TNFa), interferon-y (IFNy), macrophage-colony stimulating factor (M-CSF), and stem cell factor (SCF), either under basal conditions or after induction (25, 26, 28, 32, 42-62). Probably the most studied receptors are those for IL-1. Although not all studies completely agree on the localization of these receptors in the brain, there is a general consensus that, in adult mice and rats, IL-1 receptors are mainly concentrated in the dentate gyrus of the hippocampus. Some authors have found that these receptors are present constitutively, while others have detected them after endotoxin administration. More recently, the problem of the modulation of IL-1 receptors in the brain by glucocorticoids or adrenalectomy has been addressed. Table 3 summarizes most of the studies that have reported the presence of receptors for

different cytokines in brain tissue. Studies on the presence of receptors on isolated brain cells have not been included. B. Immune and neuro-endocrine products coexist in lymphoid, endocrine, and neural tissues

Clearly, for exerting reciprocal immune-neuro-endocrine effects, hormones, neurotransmitters, and neuropeptides must reach immune cells, and conversely, neuro-endocrine structures need to become exposed to products of activated immune cells. 1. Neuro-endocrine agents in lymphoid organs. In their physio-

logical environment, immunological cells are exposed to agents extrinsic to the immune system such as hormones, neurotransmitters, and neuropeptides. In addition to being exposed to hormones, immunological organs are innervated (63-65). For example, peri vascular plexuses within the splenic white pulp send single noradrenergic fibers between surrounding lymphocytes, and some of these nerves come in very close contact with immunological cells (65, 66). Also,

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a. Cytokines in the endocrine system. Immune-derived prod-

TABLE 2. Receptors for cytokines in endocrine glands Receptor for"

Species

Reference

Rat Mouse Mouse Mouse Mouse Mouse Pig Human Mouse Human Mouse Mouse Mouse

25 26 27 28 29 29 30 31 32 33 34 27 35

Pituitary Anterior pituitary'1 Exocrine pancreas

Mouse

Rat Rat

36 37 38

Anterior pituitary

Rat

39

Endocrine tissue/gland

IL-lo IL-1 a and /3 IL-1 (I) IL-1 (I) IL-1 (I) IL-1 (II)ft IL-1/3 IL-la IL-1 (I)6 IL-1 (I)6 IL-1 (I) IL-1 (I) IL-1 (I)6

Pituitary Pituitary Anterior pituitary Anterior pituitary Anterior pituitary Anterior pituitary Thyroid Thyroid0 Endocrine pancreas Ovary** Ovary6

IL-2 (a-chain) IL-2 IL-2 IL-6

Testi/ Testis^

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° As used here, does not distinguish receptor from binding site. 6 Indicates detection of transcripts for corresponding receptor; (I), (II) indicates receptor type. c Secondary cultures. d Transcripts found in whole ovaries and follicular aspirates. e In theca-interstitial layer of growing follicles, cytoplasma and plasma membrane of oocyte, in granulosa cells, in granulosa-luteal cells of the corpus luteum. ^In epididymis and interstitial area of the testis. 8 In interstitial cells, cytoplasm of the epithelium of epididymal ducts. h IL-2 receptors are colocalized with ACTH-positive cells.

fibers from primary sensory neurons can contact accessory cells and probably T cells at sites of inflammation and elsewhere (67). Immune cells can be exposed to hormones and neuropeptides produced by immune cells themselves. There is evidence that POMC-derived peptides, such as ACTH and /3-endorphins, can be produced by immunological cells. This was first demonstrated by the detection of ACTH-like immunoreactivity in leukocytes (68). However, it is still controversial whether this peptide is identical to ACTH of pituitary origin, whether it is inducible by CRH, and whether it is released (69, 70). It has been reported that lymphocyte-derived ACTH is insufficient to stimulate the adrenal gland in hypophysectomized mice (71) and rats (72). This is in agreement with the finding that its production is very low (72) and restricted to certain subpopulations of immune cells (73). GH and PRL have also been reported to be produced by immune cells (74, 75). As we shall discuss later, hypophysectomy results in a profound immunodeficiency. Thus, pituitary-like hormones of immune cell origin are not enough to compensate for the effects that pituitary-derived hormones exert on immune cells. The fact that these lymphocyte-derived peptides are produced by distinct subpopulations of immune cells (70,73) suggests that they may play a role in immunoregulation by exerting paracrine/autocrine actions. The same considerations may apply to neuropeptides such as VIP (76) and SP (77) that are produced by eosinophils and mast cells, in addition to being present in the innervation of immune tissues. 2. Immune cytokines in endocrine and nervous systems.

ucts may influence endocrine structures as humoral signals. However, it has also been found that some cytokines, either constitutively or after induction, are present in endocrine glands. Probably the best studied cytokine in this respect is IL-6. Mouse or rat anterior pituitary cells secrete IL-6 spontaneously (78-81). Increased production is induced, either in vivo or in vitro, by lipopolysaccharide (LPS) (80-86), phorbol myristate acetate (81), IL-1/3 (79, 82, 87, 88), TNF (87, 89), pituitary adenylate cyclase activating polypeptide (90), calcitonin gene-related peptide (90), IFNy (87), and prostaglandin E2 (82). cAMP-dependent (90) and -independent (82, 90) signal transduction pathways seem to be involved in these effects. IL-6 release is inhibited by glucocorticoids (82, 84, 91, 92). As determined by Northern blot analysis, the predominant form of IL-6 mRNA found in the pituitary after either intraperitoneal or intracerebroventricular administration of LPS seems to be different from that found in the spleen under the same circumstances (86). The presence of folliculostellate cells is essential for IL-6 production (78). Some authors have shown that, basally, the anterior and posterior pituitaries release larger amounts of bioactive IL-6 than the medial basal hypothalamus or the parietal cortex, but that the induction of the release of this cytokine by endotoxin occurs only in the anterior pituitary and hypothalamus (80). Other authors have reported that most of the IL-6-containing cells from freshly isolated mouse pituitary are positive for S-100. In contrast, neither immunoreactive nor bioactive IL-6 was found in AtT-20 cells (93). Recently, it was found that cells from the neurointermediate pituitary lobe can also secrete IL-6, and that LPS and IL-1/3 stimulate its release and the accumulation of IL-6 mRNA in these cells (94). Vasopressin and oxytocin inhibit the release of IL-6 induced by IL-1/3 and LPS from cells of the neurointermediate lobe without affecting its release from anterior pituitary cells (94). Immunoreactive IL-1/3 has been localized in the cytoplasmic granules in anterior pituitary endocrine cells and colocalized with TSH in thyrotropes. LPS induces a marked increase in anterior pituitary IL-1/3 message (95). Also, constitutive expression of TNFa mRNA and its induction by peripheral injection of LPS was demonstrated in the pituitary (96). An IL-8-like neutrophil chemoattractant is also found in rat normal anterior pituitary gland, and it can be further induced by TNFa in a dose-dependent manner (97). Regarding the presence or induced expression of cytokines in the adrenal gland, IL-1-like immunoreactivity was demonstrated in noradrenergic chromaffin cells (98). Since these cells are of neuronal type, these results are discussed in the following section. IL-6 is produced by adrenal zona glomerulosa cells; its release is stimulated by several secretagogues, including IL-la and /3, angiotensin II, and ACTH (99). The maximal release from zona glomerulosa cells is more than 10-fold greater than that from zona fasciculata/ reticularis cells. Dexamethasone, an inhibitor of IL-6 production in several tissues, has no effect on either basal or stimulated IL-6 production in the adrenal (99). Measurable levels of TNFa were found in about 50% of human fetal adrenals, but in none of the adult adrenals studied (100). We have not been able to find reports on the presence of

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TABLE 3. Receptors for cytokines in the brain Receptor for"

Species

IL-1

Rat

IL-1 IL-1/3 IL-la IL-la and /3

Rat Rat Mouse Mouse

IL-1 6

Mouse

Localization

Modulation

Ref.

IL-1 (I) IL-1 (I)6

Mouse Mouse

IL-1/3 IL-1 IL-1 (I)6 IL-1 IL-1 IL-1 (I, II) and6

Mouse Mouse Mouse Mouse

Widespread, specially dense areas: dentate gyrus (granule cell layer), pyramidal cell layer of Hip; granule cell layer of Cer, Hy Almost all neurons Hy, Cx Discrete areas High concentration: dentate gyrus (granule cells), choroid plexus meninges; low concentrations: Cx Intense signal: dentate gyrus (granule cells) weak to moderate signal: pyramidal cell layer of the hilus, CA3 region Dentate gyrus Intense signal: dentate gyrus (granule cell layer), midline raphe system, choroid plexus, endothelial cells of postcapillary venules weak to moderate signal: pyramidal cell layer of hilus and CA3 region of Hip, anterodorsal thalamic nucleus, Purkinje cells of cerebellar Cx, scattered clusters over the median eminence Hy, Hip Dentate gyrus, choroid plexus B Hip (dentate gyrus) neurons of Hip

Humai

Normal astrocytes, normal brain tissue

IL-2 IL-2 IL-4 IL-6 IL-66

Rat Rat Mouse Bovine Rat

IL-66 IL-66 IL-66

Rat Rat Rat

Hip Hip, molecular layer of Cx B Hy CA1-CA4 regions, dentate gyrus of Hip habenulae, dorsomedial and ventromedial Hy, internal capsule, optic tract and piriform Cx Hy Highest levels in Hip Pyramidal neurons, granular neurons of Hip, neurons of habenular nucleus, dorsomedial and ventromedial Hy, in piriform Cx, in scattered neurons of Cx in granular cells of Cer, in medial preoptic nucleus and lateral ventricle

TNFa TNFa p75 TNF p55 TNF

Mouse Mouse Human

Greatest in BS, less in Cer, also detected in Cx, Thl and basal ganglia Weak binding, entire B Normal astrocytes, normal brain tissue

60 61 51

IFN7 M-CSF6 M-CSF and 6 SCF and 6

Human Mouse Human Human

Normal astrocytes, normal brain tissue B Normal astrocytes, normal brain tissue Normal astrocytes, normal brain tissue

51 62 51 51

6

42 43 44 25 26 45 32 28

c d e

f

46 47 48 49 50 51 52 53 54 55 56

8 h

57 58 59

Hy, hypothalamus; Hip, hippocampus; Cer, cerebellum; Cx, Cortex; BS, brain stem; Thl, thalamus; B, brain (region not specified). As used here, does not distinguish receptor from binding site. 6 Indicates detection of mRNA for corresponding receptor; (I), (II) indicates receptor type. c Expression influenced following two injections of LPS. d Modulated by LPS, effect of macrophage depletion. c Modulated by LPS. ^Effects of LPS, glucocorticoids and adrenalectomy. * Differential expression during postnatal development. h Different expression patterns during development. 1 Studied during development. a

cytokines on the thyroid under conditions that do not involve autoimmune processes affecting this gland. In the pancreas, it has been shown that islet cells from normal mice can express TNFa mRNA if cultured in the presence of IL-1/3 (101). In the gonads, it has been found that the testis contains large amounts of IL-1 (102). IL-1 bioactivity was found in testicular interstitial fluid and cytosolic preparations (103, 104). It has been shown that the cytokine is produced by Sertoli cells (105,106) and that in vivo treatment of rats with LHs and CG induces IL-1/3 mRNA accumulation in purified

Leydig cells (107). Small quantities of bioactive TNFa were detected in conditioned medium from round spermatid fractions, and TNF mRNA is found in both pachytene spermatocyte and round spermatid fractions where it was also detected by in situ hybridization (108). The production of TNFa bioactivity by testicular macrophages has been demonstrated, while medium from cultured Sertoli cells, Leydig cells, and peritubular cells appear devoid of such activity (109). However, the bioactivity observed by assaying testicular interstitial fluid obtained in vivo could not be neutralized by antibodies to TNF (110). In vitro, it seems that the main

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source of LPS-induced TNFa is testicular interstitial macrophages (111). While some authors have not found IL-1-like bioactivity in the ovary (102), others have reported that, after LPS injection into mice, mRNA for IL-la and j3 is found in the ovary and uterus (112). After pharmacological induction of follicular maturation and ovulation, and formation of the corpus luteum in vivo, it was found that IL-lj3 mRNA is localized in theca interstitial cells (113). In patients pretreated with GnRH analogs, IL-1 bioactivity was found in granulosa and cumulus cell cultures and in follicular fluid (114), and mRNA was detected in preovulatory follicular aspirates (33). Interestingly, it was found that IL-1 in human ovarian cells and in peripheral blood monocytes increases during the luteal phase (115). In the mouse, IL-la and /3 immunoreactivity was found to be confined to the theca-interstitial layer of growing follicles and during ovulation, while during luteinization, granulosa-luteal cells of the corpus luteum demonstrated strong staining (34). Cultured human ovarian surface epithelium secrete bioactive IL-1, IL-6, CSF-1, G-CSF, and some GM-CSF, while no IL-2, IL-3, or IL-4 was detected (116). By in situ hybridization, transient expression of IL-6 mRNA was demonstrated in gonadotropin-primed hyperstimulated ovaries, with maximal mRNA levels coinciding with the period of formation of a capillary network around follicles (117). Other authors have shown that the rat ovary produces IL-6, GM-CSF, TNFa, and IL-1 before and during the ovulatory process (118). Immunoreactive TNFa was observed in granulosa cells of healthy antral and atretic follicles and appeared to be secreted by the granulosa cells (119). Immunoreactive and bioactive TNFa is present in the follicular fluid of women undergoing GnRH and CG treatment to stimulate their sexual cycles (120). TNFa mRNA was detected in rat ovary (121). In the mouse, TNFa mRNA and protein was observed in oocytes of healthy follicles (122).

Vol. 17, No. 1

nist, IL-2, IL-3, IL-6, IL-8, IL-12, and IFN7 have been found to be constitutively present in the CNS. The results are more controversial regarding the constitutive expression of TNFa. Moreover, although all reports agree that LPS administration results in further expression of IL-1 in the brain, not all of them indicate that it occurs in the same region. At least part of these discrepancies could be explained by the diverse methodology used, which ranges from immunocytochemistry or in situ hybridization to measurements of cytokine bioactivity or concentration, or expression of the corresponding mRNA, and/or by the different sensitivity of the methods. Furthermore, in reports dealing with cytokine induction in the brain, the doses of LPS administered are rather high. This is particularly relevant because this cytokine inducer can disturb the blood-brain barrier (163). In addition, the possible contribution of endothelial cells or of the blood as ^ source of cytokines in the brain has in general not been excluded. In summary, certain cytokines, either constitutively or after induction, are present in the brain. The precise localization or compartmentalization of these cytokines, and whether more physiological stimuli than those used so far 4 result in their increased central production, need still to be clarified. Cytokines in the peripheral nervous system: Regarding the

presence of cytokines in peripheral neural tissue, it has been reported that IFN7-like immunoreactivity is present in nerve terminal-like profiles in spinal cord and in a subpopulation of primary sensory ganglion cells (159). Such immunoreactivity was also found in small sensory neurons in dorsal root ganglia and in postsynaptic neurons of the sympathetic and parasympathetic nervous system (164). However, it was later concluded that the neuronal IFNy-like immunoreactive material is clearly distinct from lymphocyte-derived IFN7 (165). IL-1-like immunoreactivity was demonstrated in noradrenergic chromaffin cells of rat and mouse adrenal gland b. Cytokines in the nervous system. Cytokines in the brain: Astrocytes and microglial cells were (98). This IL-1 was shown to be biologically active. Reserpine, * which is known to deplete catecholamines, caused release of the brain cells that were first shown to produce several cythe IL-1-like immunoreactive material (98). mRNA content of tokines (123; for review see Ref. 124). More recently, it has IL-la in the adrenal gland is increased by systemic adminbeen reported that certain neurons can also produce cytokines such as IL-1 (see below). We have chosen here to review istration of cholinergic agonists, but the levels of IL-la probriefly those studies that deal not with in vitro production of tein are reduced. LPS is able to induce the expression of IL-la mRNA and protein in the adrenal gland (166). Immunorecytokines by isolated neural cells, but rather those investiactive IL-1 and IL-1 mRNA have been found in cultured gating their presence or induction in nervous tissue. The sympathetic ganglia (167). summary that follows also does not include any detailed discussion of the induction of cytokines during encephalopathies, such as those caused by brain infections. Although such studies are, of course, vital for understanding the imC. Hormones, neurotransmitters, and neuropeptides can portance of cytokines for brain pathophysiology, it is usually affect the immune system difficult to determine whether, under these circumstances, A cytokines in the brain are produced by resident cells or are Studies concerning neuro-endocrine effects on immune derived from invading peripheral immunocompetent cells. functions were performed as early as at the beginning of this Furthermore, in most cases, it is not clear whether locally century. Thus, a comprehensive review of the available ininduced immune cytokines contribute to the regulation of the formation is impossible here. Therefore, we shall provide immune response in the CNS by affecting neural mechaonly a general overview and some examples from our own nisms. laboratory. However, to provide an understanding of the Most of the reports on the presence of cytokines in the contribution of hormones, neurotransmitters, and neuropep- ~i nervous system refer to the brain (46,52,53,57,58,62,83,84, tides to immunoregulation, we will provide a more thorough 96, 125-162). Table 4 attempts to summarize these reports. discussion on the levels at which an immune response could Several cytokines, such as IL-1, its natural receptor antagobe under neuro-endocrine control.

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IMMUNE-NEURO-ENDOCRINE INTERACTIONS

71

TABLE 4. Constitutive or induced expression of cytokines in the brain Cytokine

Species

Region

Detected by

C/I

Ref.

Bioassay, ISH

c/

125

Northern IHC

/I: convulsants C/

126 127

Northern ISH; RT-PCR Northern Bioassay IHC

/I: methamphetamine C/I: LPS-IFN /I: immobilization stress Transient, during ontogeny /I: endotoxin

128 129 130 131 132

Northern EIMA Bioassay ISH RT-PCR IRMA PCR ELISA PCR IHC IHC RIA IHC Bioassay IHC

/I: transient ischemia /I: endotoxin /I: LPS icv, ip C/I: f kainic acid /I: f kainic acid C/I: t LPS C(-)/I: LPS C/I: 2 x LPS C(-)/I: LPS C(-)/I: hippocampal lesion /I: endotoxin /I: LPS C/ C(-)/I: endotoxin icv C/

133 134 135 136 137 138 139 46 139 140 141 142 143 144 145

PVN, Hip, Cer Hip, Str, Cx Median eminence Arcuate nucleus Hip, Cx, septum

ISH, HC IHC IAR

C/

c/ c/

146 52 53

Mouse Rat Rat Rat Rat Rat Rat Rat Mouse Rat Mouse

Discrete areas Cer CSF Hip, Hy, Cer Hy Anterior Hy Hip, Str, Cer, neocortex Facial nucleus Cx, Hip, Thl, Hy B PVN, Hip B

IHC/Northern Bioassay ISH, Northern RT-PCR Bioassay RT-PCR ISH RT-PCR Northern ISH, Northern Northern

/I: LPS C/ no induction by LPS C/ /I: LPS through IL-1 During development /I: axotomy facial nerve /I: kainic acid During development C/ C/

Rat Rat Rat Rat Mouse Mouse Mouse

CSF Cx, Hip, Hy, Str CSF Hy Str, Thl, Cx, Hip B Neurons of Hy Bed nucleus stria terminalis, in caudal raphe nuclei, along ventral pontine and medullary surface B, neural tube, peripheral mixed spinal nerves Brain neuroepithelium Purkinje neurons Cer Choroid plexus Ependymal cells Networks of nerve terminal-like profiles

Bioassay RT-PCR Bioassay PCR IHC Northern Western

/I: LPS icv /I: kainic acid C(-)/I: LPS icv, aged rats C/I: LPS C(-)/I: hippocampal lesion during development

a

154 137 155 96 140 151 156

Western

During development

157

Western

During development

157

IHC, ISH IHC, ISH IHC

/I: LPS /I: LPS C/

158 158 159

IL-1/3

Rat

IL-1/3 IL-1/3

Rat Rat

IL-1/3 IL-1/3 IL-1/3 IL-1/3 IL-1/3

Rat Rat Rat Rat Rat

IL-1/3 IL-1/3 IL-1 IL-1/3 IL-1/3 IL-1/3 IL-1/3 IL-1/3 IL-la IL-la IL-1/3 IL-la, /3 IL-1/3 IL-1 IL-1/3

Rat Rat Rat Rat Rat Rat Mouse Mouse Mouse Mouse Rabbit Rabbit Pig Cat Human

IL-lra IL-2 IL-2

Rat Rat Rat

IL-3 IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 IL-8 IL-12 (p35) TNFa TNFa TNFa TNFa TNFa TNFa TNFa

TNFa

Mouse

TNFa

Chicken

TNFa TNFa IFNy

Pig Guinea-pig Rat

Granule cells dentate gyrus pyramidal cells Hip, granule cells Cer granule/periglomerular cells, olfactory bulb, dispersed cells VMH; FCx Cx, Thl, Hy, Hip Periventricular medial Hy, Hip and olfactory tubercle Hy Forebrain Hy B Meninges, choroid plexus brain blood vessels, non-neuronal cells in parenchyma Cx, Hip, Str, Thl Hy BS, diencephalon (extracellular) Several regions Cx, Thl, Hip Hy Str, Thl Hip, Hy Hip Str, Thl, Cx, Hip OVLT B Hip and blood vessels CSF from third ventricle Hy

c/

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147 148

83,84 57 149 58 150 137 151 152 153

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TABLE 4. Continued Cytokine

Species

Region

Detected by

C/I

Ref.

IFNy Rat Facial nucleus /I: axotomy facial nerve 160 IHC M-CSF Mouse Granule cells Cer RNase protection C 161 M-CSF B Mouse Si-analysis From ED 13 to adulthood 62 B CSF-1 Mouse Northern During development 151 TGF/32 Mouse B Northern During development 151 Cx TGF/3 Rat Northern C/ 162 Hy, Hypothalamus; Hip, hippocampus; Cer, cerebellum; Cx, cortex; FCx, frontal cortex; CSF, cerebrospinal fluid; OVLT, organum vasculosum lamina terminalis; BS, brain stem; PVN, paraventricular nucleus; Str, striatum; Thl, thalamus; B, brain (region not specified); ISH, in situ hybridization; HC, histochemistry; IHC, immunohistochemistry; IAR, immunoautoradiography; Northern, Northern blot analysis; Western, Western blot analysis; IRMA, immunoradiometric assay; EIMA, enzyme amplified immunometric assay; \ , increased; ED, embryonic day; C/, constitutive expression; C(—), not found constitutively; I, expression induced by; icv, intracerebroventricular.

1. Endocrine effects on the immune system. Investigations into

the participation of hormones in the immune response have generally involved either the parenteral administration of hormones, antagonists, and blockers, or the ablation of endocrine glands. Numerous reports agree that hormone administration can lead to depressed or stimulated immune responses, depending on the kind and dose of hormones and the timing of their administration. In general, glucocorticoids, androgens, progesterone, and ACTH depress the immune response in vivo, whereas GH, PRL, T4, and insulin increase the response (168-179). Gender differences in the immune response are well documented. Females develop stronger immune responses, have higher immunoglobulin concentrations, and are more resistant to the induction of immunological tolerance than males (for review see Refs. 170 and 180). Furthermore, the incidence of certain autoimmune diseases is higher in females (181). Opioid peptides, particularly j3-endorphin and Met-enkephalin, have also been implicated as immunomodulators since they can affect several immune mechanisms. However, it is difficult to conclude whether, as a whole, these peptides are immunosuppressive or immunostimulant since the effects reported differ depending on the type of immune process studied, on the cell source and type, on the species, on the concentration of the opioid peptide used, and on experimental conditions, i.e. in vivo or in vitro. An analytic discussion of this subject is beyond the scope of this article (for review see Refs. 180 and 182). Hypophysectomy suppresses hematopoiesis and immune cell proliferation and causes atrophy of lymphoid organs and a progressive deterioration of all immune functions (for review see Ref. 183). Immunodeficiency in hypophysectomized animals can be reversed by PRL, GH, and placental lactogens, but not by other pituitary hormones (176, 183). Administration of bromocriptine, which specifically blocks PRL release, causes immunodeficiency. PRL administration has been shown to reverse this effect. This hormone has also been shown to stimulate immune parameters in normal animals (184). It has been shown that PRL mRNA is expressed in mitogen-stimulated lymphocytes (74), and that addition of a specific antibody to PRL to the culture medium results in inhibition of lymphocyte proliferation (185). However, the inhibitory effect of hypophysectomy on immune functions in vivo cannot be counteracted by the lymphoid cell-derived PRL. The other pituitary immunostimulatory hormone is GH, which has been shown not only to enhance immune

responses but also to delay aging of the immune system (186). ACTH has been reported to inhibit different immune functions independently from its capacity to stimulate glucocorticoid output (174, 187). The inhibitory effect of adrenocorticoid hormones in a variety of immune and inflammatory mechanisms has resulted in their widespread therapeutic application. However, most of the evidence derives from pharmacological studies, and less is known about the effect on immune functions of fluctuations of endogenous levels of glucocorticoids. For example, in animals kept under conventional conditions but without further antigenic stimulation, we studied the relationship between endogenous glucocorticoid blood levels and the number of splenic B lymphocytes secreting immunoglobulins at a given time (188). A clear inverse relationship between the values of corticosterone in blood of adrenalectomized, sham-operated, and stressed mice and the number of antibody-secreting cells in the spleen is observed. An approximately 10- to 15-fold variation in glucocorticoid blood levels was paralleled by oscillations of the same magnitude in the number of antibody-secreting cells (10-fold). These data show that endogenous levels of glucocorticoids contribute to the control of B cell activity. Since most immune responses involve the cooperation between T and B lymphocytes, we can conclude that the pituitary-adrenal axis affects the overall activity of the immune system. 2. Neural effects on the immune system. Data on the effects of

autonomic nervous system mediators on the immune system are contradictory, but in the main they indicate that neurotransmitters can influence the immune response, both in vitro and in vivo (11,16,189-194). We (195) and others (196) have observed that neonatal sympathectomy with 6-hydroxy-dopamine enhances the immune response to several antigens. A similar effect was also observed in adult rats after surgical denervation of the spleen. However, adult chemical sympathectomy had the opposite effect (197-199). We recently found that chemical denervation at birth results in increased numbers of immunoglobulin-secreting cells in the spleen of adult mice that were kept under conventional conditions but did not receive further antigenic stimulation (200). Because neonatal administration of 6-hydroxydopamine results in a permanent destruction of sympathetic nerve endings, the results strongly suggest that there is a permanent increase in the activity of splenic B lymphocytes in mice deprived of sympathetic innervation. Furthermore, these results agree with the reported enhancing effects of sympathectomy on

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antibody-forming cells in immunized animals. Since 6hydroxy-dopamine administered at birth not only interferes with the sympathetic innervation of peripheral organs but also with central noradrenergic neurons, our studies do not allow definitive conclusions about which of these structures affects the function of B cells. However, these studies reveal the relevance of central and autonomic mechanisms in immunoregulation under basal and activated conditions. Parasympathetic agents have also been reported to affect antibody formation and cytotoxicity (194, 201, 202). Several neuropeptides can affect immune cell activity. For example, SP enhances B cell production of immunoglobulin M (IgM) and immunoglobulin A (IgA), but not of IgG (203). SOM and VIP have opposite effects on B cells and also inhibit T cell proliferation (204). SP, SOM, and VIP stimulate mast cells to release mediators of hypersensitivity such as histamine and platelet-activating factor (PAF) (205). SP also has a stimulatory effect on specific immune responses (206-208). The overall picture indicates that, in general, SP exerts stimulatory effects while VIP, SOM, and neuropeptide Y inhibit immune functions (204, 209-211). There is also abundant evidence showing that direct manipulation of the brain, e.g. electrolytic lesions or stimulation of different parts of the brain, can affect the immune response (212-216). The effects on the immune response caused by stress (217-221) and circadian rhythms (222), and the complex phenomena of conditioning of the immune response (223-227), also show that processes integrated at the level of the CNS can affect immune functions.

73

growth factors. For example, during an immune response, accessory cells must process the antigen to present it appropriately to lymphocytes, which transform into blasts and undergo clonal expansion after receiving this information. These and other immune processes, such as phagocytosis, cell migration, and homing, are mechanisms involving high metabolic demands. Since lymphocytes are the only cells that need to proliferate to reach the mass necessary to fulfill their specific functions, they are particularly influenced by neuroendocrine signals that control intermediate metabolism (228). Two main pathways, one involving cAMP and the other inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) as second messengers, are used by hormones, neurotransmitters, and neuropeptides for intracellular signal transduction. There is evidence that these pathways are also used by certain cytokines, antigens, or mitogens when they bind to their respective receptors in immune cells. For example, binding of an antigen to its specific T cell receptor (229) or addition of IL-2 to cell lines that depend on IL-2 for growing (230) results in activation of phospolipase C, yielding IP3 and DAG as intracellular second messengers. It is also clear that the T cell antigen receptor and interleukin receptors utilize G proteins as an initial transducer to amplifier systems (230). Whether these G proteins are unique or are also used by hormone receptors is not known. It is beyond the scope of this article to review this matter in detail (for review see Refs. 229-232). However, it seems likely that neuro-endocrine and immune-mediated stimuli share mechanisms for intracellular signal transduction. The evidence in support of this pos3. Immune mechanisms that can be affected by neuro-endocrine sibility is still very fragmentary, and much more work is still agents. The evidence discussed above shows that hormones, needed in this particular area. Nevertheless, we wish to emneurotransmitters, and neuropeptides can affect the activity phasize this aspect here since immune cells are probably, of the immune system. Most of these studies evaluated the except for neurons, the cells that are exposed to the most influence of neuro-endocrine signals on the immune system diversified array of signals from inside and outside the orwith respect to either the proliferation of immune cells or the ganism. Furthermore, since immune cells are mobile, they final effector mechanism, such as the production of antibodare also exposed to locally generated mediators in the difies or the activity of cytotoxic cells. The generation of specific ferent microenvironements where they circulate or are loeffector cells and molecules of the immune system can be cated. The common use of intracellular transduction signals influenced at several levels. These levels range from very by hormones, neurotransmitters, neuropeptides, and imgeneral processes, such as the intermediate metabolism of mune ligands would provide a molecular basis for synerimmune cells, to more specialized mechanisms, such as the gistic and antagonist effects of neuro-endocrine and immune selection of cells that can recognize a huge repertoire of agents on the immune response. In addition, the convergence antigens, and the production of the cytokines that support of different types of stimuli that do not share the same inlymphoid cell growth and differentiation. Furthermore, the tracellular signaling pathway may contribute to interactions efficiency of an immune response depends also on the conbetween immune and neuro-endocrine agents. For example, trol of processes such as the proliferation of cells with low stimulation of the T cell receptor results in activation of the affinity for the antigen, the interaction between immune cells phosphoinositide pathway without affecting the levels of and their targets, and the mobility, migration, and homing of cAMP. However, the increase in intracellular levels of cAMP these cells. The following is a discussion on the effects of induced by stimulation of /3-adrenergic receptors in lymhormones, neurotransmitters, and neuropeptides on some of phocytes is further enhanced if the T cell receptor is also these processes. stimulated (229). Since an increase in intracellular cAMP levels inhibits proliferation, this may explain the fact that a. Intermediate metabolism and intracellular signal transduction in immune cells. The control of the metabolism of immune stimulation of /3-adrenergic receptors at the time of lymphocyte activation ultimately results in a decreased proliferative cells and the concentration of second messengers used for intracellular signal transduction, e.g. cAMP, can be affected response. by neuro-endocrine signals. These mechanisms are specially In summary, the outcome of the biochemical events inisensitive to neuro-endocrine signals due to some peculiaritiated in a lymphocyte after recognition of an antigen or ties of immune processes. induced by a cytokine would, in fact, depend on other intracellular signals resulting from the simultaneous binding Immune cells are highly dependent on nutrients and

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dorphin and enkephalins, affect mononuclear cell mobility of neuro-endocrine ligands that occur under physiological or (243-247). pathological conditions. b. Negative and positive selection of lymphocytes during on-T and B lymphocytes express higher numbers of receptor t togeny. During ontogeny, the precursors of T lymphocytes for neuropeptides such as SP and SOM when they are located in lymphoid tissues than when they circulate in the blood expressing receptors with high affinity for self-antigens are (248, 249). It has been shown that down-regulation of VIP eliminated (negative selection), and those with low affinity receptors in T lymphocytes reduces their homing in tissues; are stimulated to become mature T cells (positive selection). this is possibly evidence for selective trapping of lymphoThis selection occurs mainly, but not exclusively (233, 234), cytes expressing more receptors for these neuropeptides in the thymus. Programmed cell death, or apoptosis, is a (241, 242). It is, therefore, likely that lymphocytes are more J process of selective cell deletion that contributes to the essensitive to neuropeptides when they are located in regions tablishment of tolerance to self-antigens. Stimulation of T cell in which they are more exposed to these nerve mediators. receptors in immature thymocytes leads to apoptosis. ExpoControl of gene expression and production of cytokines and e. sure of these cells to glucocorticoids results in a similar phereceptors. The production of several lymphokines and their nomenon. However, the induction of apoptosis is prevented monokines, which are necessary for cell differentiation, when these two events occur simultaneously. It was recently transformation, and clonal expansion, and the expression of j reported that thymic epithelial cells can produce steroids their respective receptors can be affected by neuro-endocrine (235). Glucocorticoids produced in the thymus are capable of signals. Most available reports consider the glucocorticoids antagonizing the apoptosis induced by stimulation of those and their effects on IL-1, IL-2, IL-4, TNFa, CSF, and IFNy T cell receptors that bind with low affinity to self-antigens in production (250-256). All the studies mentioned, with the the thymic epithelium. By these means, glucocorticoids exception of the one on IL-4, show that glucocorticoids inwould favor positive selection in the thymus. This is a prohibit cytokine production. Only a few reports consider horvocative hypothesis, but one should consider that circulating monal effects on the expression by immune cells of receptors < steroids derived from the fetal adrenal gland may also confor lymphokines and monokines. Glucocorticoids induce extribute to both negative and positive selection (236). Other pression of IL-1 receptors predominantly on B cells (257), neuropeptides present in the thymus, such as oxytocin and while dexamethasone does not affect the number and affinity vasopressin, could contribute to the selection process and of IL-2 receptors (258). In human monocytes, IL-6 receptor promote thymocyte differentiation (237, 238). mRNA levels have been shown to decrease in response to c. Contribution to immunospecificity. The specificity of an glucocorticoids (259). With regard to effects of other horimmune response to an antigen is based on the stimulation mones, it has been shown in monocytes that both TNF reof those lymphoid cells that possess high affinity receptors ceptors and TNF production are decreased by insulin (260), -J for the antigen. However, other processes that can occur and that PRL induces IL-2 receptors on unfractionated during an immune response may affect such specificity, e.g. splenocytes (261). There are also studies showing that certain the binding of the antigen to cells expressing receptors with neurotransmitters and neuropeptides influence the produclow affinity and the polyclonal stimulation of cells by certain tion of cytokines. Noradrenaline (NA) has been shown to cytokines. There are mechanisms by which hormones and decrease IL-1 production (262), whereas a2-adrenergic agoneurotransmitters can contribute to make the immune renists increase TNF release by LPS-stimulated macrophages sponse more specific. These mechanisms are based on pref(263). SOM and VIP decrease IFNy; SP and substance K 4 erential effects of these agents on either resting or activated produce an increase in IL-1, TNF, and IL-6 release from cells and are related to the stage of the immune response human peripheral blood leukocytes (264, 265); and SP induring which the neuro-endocrine mediators are released. duces an increase in IL-2 activity (266). There are few studies Since this aspect is linked to the participation of neuro-enregarding the influence of neurotransmitters and neuropepdocrine mechanisms in immunoregulation, it will be distides on the expression of receptors for cytokines on immucussed in more detail in Section III. C. nological cells. Adrenaline and SOM reduce receptors for ,1 d. Immune cell recirculation and homing. The circulation ofTNF on monocytes (260); /3-adrenergic agonists induce a immune cells, as well as their traffic through and within reduction of IL-2 receptors in lymphocytes (267); and SP lymphoid structures and homing in tissues, is essential to enhances IL-2 receptors in gut-associated lymphoid tissue immunosurveillance and to an efficient immune response. (266). These processes can be affected by neuro-endocrine agents. /. Immune cell interactions and autoregulatory mechanisms of Catecholamines cause increased outflow of lymphocytes the immune response. It is well established that T lymphocytes and granulocytes from the spleen of normal guinea pigs recognize an antigen when it is expressed on the surface of ^ (239). In immunized animals, adrenaline causes a selective a cell in association with self-markers that belong to a group release of antibody-producing cells from this organ (240). of molecules known as the major histocompatibility complex (MHC). For example, cytotoxic T cells recognize an antigen Neuropeptides derived from nerve fibers in lymphoid oronly if it is presented in combination with MHC molecules gans and in other tissues where an immune response may of a given class (class I), and T helper cells only if it is take place can also affect immune cell traffic and migration. associated with class II MHC molecules. Thus, the recogni- . VIP infusion reduces the outflow of lymphocytes in the efferent lymph of cannulated lymph nodes (241, 242). In vitro, tion of MHC markers is crucial for antigen presentation and for an effective communication between different types of it has also been shown that several neuropeptides such as VIP, SP, bombesin, and arginine-vasopressin, as well as /3-en- immune cells and between immune cells and their targets.

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There is some evidence that hormones can directly, or indirectly, influence the expression of class I and II MHC molecules in immunological cells and their targets. For example, glucocorticoids affect cytokine-mediated expression of class I and II MHC antigens on macrophages (254, 268, 269). Neurotransmitters and neuropeptides can also influence MHC expression. There is evidence that noradrenaline (NA) and VIP can inhibit the expression of class II molecules on antigen-presenting cells in the brain (270, 271). For an efficient immune response, the quantitative relation between different types of immune cells, for example helper (CD4+) and cy to toxic (CD8+) T lymphocytes, must be appropriated. As mentioned before, this can be affected by glucocorticoids and sympathetic neurotransmitters (13, 272, 273). Regulatory interactions between antibody classes can also be modulated by neuro-endocrine agents. The antibody switch between IgM and IgG can be influenced by glucocorticoids (274, 275). SP stimulates the production of IgM and IgA (203). VIP and SOM oppose this effect (276). Idiotypes are certain regions of the antibody molecule, close or within the antigen-combining site, that can elicit the production of other antibodies (anti-idiotypes). Interactions between idiotypes and anti-idiotypes form the basis of a refined autoregulatory mechanism of the immune response called the idiotypic network. The degree of connectivity within this network can also be affected by neuro-endocrine agents since, as mentioned before, the number of antibodysecreting cells in animals that were not intentionally immunized is inhibited by glucocorticoids and sympathetic neurotransmitters (188, 200). D. Immune cell products can affect neuro-endocrine mechanisms From the previous discussion it is clear that hormones, neurotransmitters, and neuropeptides can affect immune functions. The evidence that this is reciprocated and that immune cell products can affect neuro-endocrine mechanisms will be reviewed in this section. We approached this question by studying whether factors released by immunological cells after in vitro stimulation were capable of inducing in vivo neuro-endocrine effects. Upon injection into normal animals, the supernatants, obtained from cultures of allogeneic and/or mitogenic stimulated human or murine lymphocytes, evoked an increase in ACTH and corticosterone output (277, 278). The products that mediated these effects were generically termed glucocorticoid-increasing factors. The fact that 1 million lymphocytes stimulated in culture produce enough glucocorticoid-increasing factors to induce a several fold increase in ACTH and corticosterone levels in the blood of normal animals illustrates their potency. Later, we showed that these conditioned media were also capable of decreasing the NA content of the hypothalamus (279). These results fully confirmed our prediction that factors derived from immune cells can affect neuro-endocrine mechanisms (280, 281). Later, pure or recombinant immune cytokines became available, and it was possible to test their capacity to influence endocrine and neural functions. In the

75

following, we shall attempt to provide an overview of the enormous bulk of information that has been published on this matter during recent years. 1. Effects of immune-derived products on endocrine

mechanisms,

The capacity of IL-1 to stimulate the hypothalamus-pituitaryadrenal (HPA) axis is the most extensively studied example of the influence of cytokines on endocrine functions. Both the purified natural and the recombinant human forms of IL-1 can stimulate ACTH and corticosterone output in mice and rats. Also, IL-1 appears as the most likely mediator of the glucocorticoid changes induced by certain viruses (282). This effect of IL-1 seems to be rather specific since it is not paralleled by changes in other "stress hormones," such as somatotropin, PRL, and a-MSH. The levels of catecholamines in blood are only modestly increased after IL-1 injection (283). As will be discussed later, although the main site of action of IL-1 is the hypothalamus, it can also affect ACTH released during long term cultures of normal pituitary cells. It has also been shown that IL-6, TNFa, and IFN7 stimulate the pituitary-adrenal axis (284-286). Another factor that increases plasma corticosterone levels in vivo is thymosin fraction 5 (287). Comparative studies on the capacities of IL-1, IL-6, and TNFa to stimulate the pituitary-adrenal axis showed that IL-1 is more potent than TNFa and IL-6 (288). After this initial evidence that lymphokines and monokines can affect the pituitary-adrenal axis, further studies on this effect and on other neuro-endocrine mechanisms have been performed. The effect of several cytokines on the hypothalamus-pituitary axis in vivo is summarized in Table 5, which includes some specific details (282-336). Generally, IL-1, TNF, and IL-6 exert an inhibitory effect on the hypothalamus-pituitary-thyroid axis. Regarding the hypothalamus-pituitary-gonadal axis, it is worthwhile to mention that IL-1 induces a decrease in LHRH and LH concentrations only if the cytokine is administered centrally. This indicates that the actions of IL-1 on plasma LH levels are most likely mediated within the brain (321). However, IL-1 may also affect sexual steroid production by acting directly on the gonads (see below). Another effect of IL-1 that is observed only when IL-1 is injected intracerebroventricularly is an increase in PRL and GH plasma levels. Although these experiments are pharmacological, they are, in our view, valuable for assessing the potential physiological neuro-endocrine effects of cytokines since they were performed in vivo. A large number of studies have also been performed in vitro (36, 87, 89, 337-359). These results are summarized in Table 6. The evidence is sometimes contradictory as seen from the effects of IL-1 on ACTH and PRL release and the effects of TNF on GH and PRL release. This is probably due to the different in vitro systems used and to different culture conditions. However, as a whole, the evidence indicates that IL-1, IL-2, IL-6, TNFa, and IFN7 can also directly affect the pituitary gland. The effect of cytokines on the adrenal (40, 100, 360-371) gland is summarized in Table 7. The majority of these studies derive from in vitro work since the aim was to study direct effects of the cytokines on the adrenal. The results indicate that IL-1, IL-2, and IL-6 can increase the release of glucocorticoids. Regarding the effect of cytokines on aldosterone se-

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TABLE 5. In vivo effects of cytokines on the hypothalamus-pituitary axis Cytokine

Species

Route

Endocrine effect ACTH, [ t corticosteronel ACTH ACTH, [ | corticosterone] (sex and strain dependent) ACTH, [ | corticosterone] CRF, t ACTH ACTH, | CRH and T mRNA CRH (in hypothalamus) mRNA CRH (in PVN), f ACTH, [ | corticosterone] mRNA POMC (in pituitary) ACTH, [ 1 corticosterone] ACTH ACTH, [ 1 corticosterone] ACTH, [ f corticosterone] ACTH, [ f corticosterone] ACTH (in pituitary) t CRH (in hypothalamus) ACTH ACTH, [ | corticosterone] (blocked by a-MSH) ACTH, t vasopressin ACTH, [ | corticosterone] ACTH, [ f corticosterone] ACTH ACTH, [ t corticosterone] mRNA CRF, | CRF (PVN) ACTH, [ 1 corticosterone], age dependent GH, t PR, I TSH LH TSH, [ | free T4; | T4-binding prealbumin levels I LH-RH(ME), | LH LH, | FSH, | PG (disruption estrous cycle) LH, | PRL (blocked by a-MSH) LH, | FSH, [ t cortisol] (blocked by CRH antagonist) PRL

Ref.

IL-1/3 IL-la IL-la,/3 IL-1/3 IL-1/3 IL-la,/3

Mouse Mouse Mouse Rat Rat Rat

ip ip ip ip ip ip

| f f f t t

IL-1/3

Rat

ip

IL-la,/3 IL-1/3 IL-1/3 IL-1/3 IL-1/3 IL-1/3 IL-la IL-la

Rat Rat Rat Rat Rat Rat Rat Rat

iv iv iv icv

IL-1/3

Rat

IL-1 IL-1/3 IL-1/3 IL-10 IL-10 IL-1/3 IL-1 IL-la,/3 IL-1/3 IL-1/3 IL-1/3 IL-la IL-la

Rat 10-day rat Rat Rat Rat Rat (neonate) Rat Rat (cast) Rat Rat Rat Monkey (ov) Monkey (ov)

icv icv

| f t t t t f t t f j f f t f f f f | 4 | I i i

IL-1/3

Pigeons

icv

t

IL-2 IL-2

Rat Pigeons

ip icv

t mRNA POMC (in pituitary) t PRL

329 328

IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 IL-6

Mouse Rat Rat Rat Rat Rat Rat

ip iv iv iv ip icv

icv

t t f t f t t

ACTH ACTH, ACTH, ACTH ACTH, ACTH ACTH,

291 284 288 303 300 330 331

TNFa TNFa TNFa TNFa TNFa

Rat Rat Rat Rat Human

iv iv iv icv iv

t t | t t

ACTH, [ | corticosterone] ACTH TRH (in hypothalamus), 4 TSH, [T4, free T4, T3] ACTH, t GH LH, 1 FSH, [ | testosterone]

ip, icv iv (r) iv (r) icv iv, icv ip minip ip icv

ihyppoc icv ip icv icv

ip (minip) icv

icv (prl)

282, 289, 290° 291 292 293, 2946 295, 296, 297, 298 299 300 301, 302, 288 303, 304, 305c 306d 307c, 308 309/" 310 310 311 312

313 314 315 316 317* 318 319 320, 321, 322* 323 324 325 326 327 328

t CRH [ f corticosterone] [ t corticosterone] | TSH

301, 332, 288 285, 333' 334 335 336

[] Indicates peripheral hormone evaluated in parallel. POMC, proopiomelanocortin; PVN, paraventricular nucleus; ME, median eminence; ov, ovariectomized; cast, castrated; (r), repeated injections; prl, prolonged treatment; i hippoc, intrahippocampal; minip, minipump; | , increase; 1, no change; 1, decrease. a Effect inhibited by a-MSH. 6 Effect is age, gender, and sex steroid dependent. c Capsaicin desensitization reduces the IL-1-induced increase in plasma ACTH. d Effect increased by blockade of nitric oxid syntethase. c Effect blocked by 6-OH-DA or a-adrenergic antagonist. f Effect inhibited by mediobasal hypothalamic deafferentation. 8 Studies in different strains. h Effect blocked by naloxone. 1 Effect mediated by prostaglandins.

cretion, the results obtained in vivo and in vitro are contradictory. It has been reported that IL-1 and TNF inhibit angiotensin- and ACTH-induced aldosterone secretion in cultures of adrenal cells. However, we have observed that, after intravenous administration of IL-1 to rats, a marked

increase in aldosterone blood levels is detected in parallel to elevated levels of ACTH and PRA (304). Reports on the effect of cytokines on the thyroid gland are summarized in Table 8 (323, 334, 372-386). The results show that IL-1 and TNFa inhibit thyroid functions in vivo and in vitro.

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77

TABLE 6. Effects of cytokines on the pituitary in vitro Cytokine

System

Effect

IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1

AtT-20 cells Pituitary cell cultures Pituitary cell cultures Pituitary cell cultures Pituitary cell cultures Superfusion pituitary cells Perifusion pituitary cells Pituitary cell cultures Pituitary cultures Superfused neurohypophysis Pituitary cells Pituitary cells Anterior pituitary perifusion

IL-1

Pituitary cultures

t ACTH t ACTH, LH, GH, TSH, | PRL t ACTH, no change in LH, GH, FSH and PRL f ACTH, not change in LH and GH f ACTH (only if long term cultures) No effect on ACTH t ACTH, LH, GH, TSH, PRL (very quick effects) I TSH-induced PRL release 4 PRL f Vasopressin, | oxytocin" t PRL 4 FSH, t LH No effect on ACTH secretion, although confirm effect in vivo No effect on ACTH

IL-2

Pituitary cells

t ACTH

IL-6 IL-6 IL-6 TNFa

Pituitary Pituitary Pituitary Pituitary

TNFa TNFa TNFa TNFa TNFa TNFa TNFa

Pituitary cells Pituitary cells Pituitary cells Pituitary cells Pituitary cells Pituitary cells Anterior pituitary cells

t PRL f PRL, GH and LH No effect on ACTH 1 ACTH, PRL, and gonadotropins (not later than 30 min) T GH 4 GH 4 CRH-induced ACTH release (long term cultures) t PRL No basal effect, 4 TRH-stimulated TSH secretion t PRL 4 PRL (more pronounced if combined with IFNy) no effect on TSH

IFN7

Pituitary cell cultures

IFNy

Anterior pituitary cells

cells cell cultures cultures cells

4 Hypothalamic releasing factor-induced release of ACTH, PRL and GH

t PRL

Ref.

337 338 339 340 341 342 343 344 345 346, 347 348 349 350 351 36 348 352 351 353 89 354 355 356 357 348 358 359

87

f , Increase; 4 , decrease. a Electrically evoked release.

Effects of cytokines on the endocrine pancreas in vivo are difficult to evaluate because of the profound metabolic action of some of these mediators (see Section D.3.). The results from in vitro experiments are controversial. It has been reported that IL-1 can either stimulate or inhibit insulin release by isolated rat islets depending on the dose used (387, 388). Using isolated perfused pancreas, it has also been found that IL-1 increases insulin release in response to glucose (389,390) and stimulates glucagon secretion irrespective of increasing glucose and insulin concentrations (390). Glucose-induced insulin secretion was potentiated in pancreases obtained from rats after in vivo administration of IL-1 (391), while glucagon secretion in response to an arginine stimulus was not affected (392). In contrast, other authors have reported that IL-1, TNFa, and IFN7 inhibit both j3- and a-cell-secretory functions in islet monolayers, while only IL-1 and TNF produced sustained decreases in insulin and glucagon content in islet cultures (393). In isolated human islets, IL-1, TNF, and IL-6 inhibit insulin release in response to high doses of glucose and almost completely block basal glucagon release (394). However, a proper evaluation of these results must consider that some of these cytokines can be cytotoxic in vitro (393, 395). Effects of IL-1, IL-2, and TNF on testis and ovary have also been studied. In vitro, IL-1 stimulates progesterone release

(396,397), while TNF exerts an opposite effect (398,399). IL-1 and TNF inhibit gonadotropin-induced estradiol production (114, 400). IL-1 (401) and IL-2 (402) inhibit gonadotropininduced testosterone synthesis. Other authors have reported that IL-2 and IFNy decrease LH-induced testosterone production in isolated Leydig cells, but IL-2 increases testosterone production in minced murine testis (403). TNF stimulates testosterone secretion in vitro (404) but inhibits the production of this hormone in vivo (336, 405). Interestingly, it has been recently shown that conditioned medium from macrophage cultures inhibit testosterone production by Leydig cells in vitro (406, 407). In this section, we often referred to effects of cytokines on endocrine glands in culture. These studies were performed to obtain evidence for direct effects of these mediators on hormone production. However, it is necessary to consider that cytokine actions are primarily exerted in a paracrine fashion, and that these mediators can act as growth factors and nonspecifically influence cell metabolism. Thus, some of the effects described cannot be interpreted as "endocrine actions" of cytokines since they might reflect effects that occur when they are locally produced in the tissues (for example, during inflammatory and autoimmune processes). In contrast, the data obtained in vivo clearly show that certain

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BESEDOVSKY AND DEL REY

78 TABLE 7. Effects of cytokines on the adrenal gland Cytokine

System

Effect

Ref.

IL-1 a,/3 IL-1 IL-10 IL-1 IL-1 IL-1/3 IL-1 IL-1/3 IL-1 IL-la

Quartered adrenal, dispersed cell cultures Human adrenal cell and organ culture In situ perfusion Human adrenal cells Bovine adrenal cells Adrenal slices Rat adrenal cells Isolated zona glomerulosa, capsular strips Chromaffin cells Adrenal cells

360 361 362 363 40 364 365 366 367 368

IL-1/3

Glomerulosa cells

| Corticosterone No effect on cortisol f Corticosterone (mediated by PG) f Cortisol (more effect with monocyte supernatant) f Cortisol (mediated by PG) f Corticosterone f Corticosterone (mediated by PG) I Angiotensin-induced aldosterone secretion t VIP, 4 Met-enkephaline I Epinephrine, f corticosterone (a-adrenergic mediated, not mediated by PG) 4 Angiotensin-induced aldosterone secretion

IL-2

Rat adrenal cells

| Corticosterone (mediated by PG) (effect only with rat IL-2, not with human IL-2)

365

IL-6 IL-6

Adrenal cultures Rat adrenal cells

t Corticosterone f Corticosterone (mediated by PG)

370 365

TNFa TNFa TNFa TNFa IFN 7

Chromaffin cells Human fetal adrenal Glomerulosa cells Human fetal adrenal Human fetal adrenal

f f 4 4 I

367 371 369 100 371

VIP, | Met-enkephaline mRNA insulin-like growth factor II Angiotensin and ACTH-induced aldosterone Cortisol, shift to androgen production mRNA insulin-like growth factor II

369

PG, Prostaglandin; f , increase; 4 , decrease.

cytokines can serve as mediators in the bidirectional communication between the immune and endocrine systems. Apart from cytokines, other potential immunological messengers capable of influencing neuro-endocrine processes are histamine, serotonin, and serotonin precursors, which are released during certain immune responses (10); the pituitary hormone-like peptides that are produced by stimulated lymphoid cells (68,408,409); and thymic hormones, vasopressin, and oxytocin, which can be produced by thymic nurse cells (238, 410). Antibodies can also be candidates for mediating immune-neuro-endocrine interactions since the Fc part of immunoglobulins has been shown to bind to pituitary ACTH-producing cells (411). Even specific antibodies can affect the endocrine systems. For example, antihormone antibodies can share common characteristics with hormone receptors, and the anti-idiotypic antibody may act as the ligand, thereby behaving as an internal "image" of the hormone. This mechanism could explain the appearance of autoantihormone antibodies and antihormone-receptor antibodies during different autoimmune diseases (412, 413). Antibodies have also been shown to modify hormonal action, e.g. by changing the affinity of the hormone for the carrier, by protecting hormones from enzymatic degradation, and by stabilizing particular conformations in the molecule (414). 2. Effects of immune-derived products on the nervous system. The

effects exerted by lymphokines and monokines on neuroendocrine mechanisms imply that these products can directly or indirectly affect neural functions. a. Effect of cytokines on the production ofhypothalamic releasing

factors. The first hypothalamic releasing factor whose production was shown to be affected by a cytokine was CRH (295-297). IL-1, whether administered systemically or intracerebroventricularly or applied in vitro (415, 416), stimulates CRH production in the hypothalamus. This finding and

other effects of cytokines on hypothalamic releasing factors have been included in Table 5. b. Effect of cytokines on CNS neurotransmitters

and central

neuronal activity. We have shown that administration of immune cell-conditioned media containing lymphokines and monokines results in decreased NA content in the brain (279). A summary of effects of natural purified or recombinant cytokines on brain neurotransmitters and central neuronal activity is given in Table 9 (52, 316, 324, 417-446). IL-1 reduces NA content and increases the ratio of 3-methoxy-4hydroxyphenylethylene glycol/NA, which reflects increased NA metabolism. This effect is observed in the hypothalamus, hippocampus, brain stem, and spinal cord. The fact that catecholaminergic fibers in the spinal cord are stimulated by IL-1 may indicate one neural pathway for the effect of this cytokine in the CNS. The stimulation of NA neurons in the CNS by IL-1 is consistent with other evidence showing that stimulation of CRH production by catecholaminergic neurons is involved in the response of the HPA axis to IL-1. This is further supported by studies showing that the response of the HPA axis to IL-1 is blocked by surgical interruption of noradrenergic innervation of CRHproducing neurons in the paraventricular nucleus of the hypothalamus or by NA antagonists (307,309,447,448). IL-1 and IL-6 stimulate dopamine metabolism in the striatum, hippocampus, and prefrontal cortex. These cytokines also stimulate serotonin metabolism and release, but the effect is observed predominantly in the hippocampus. However, IL-1 causes a general accumulation of tryptophan in the CNS. IL-2 inhibits potassium-induced release of acetylcholine from slices of the hippocampus. IL-3, IFNy, G-CSF, and GMCSF augment choline-acetylcholine transferase activity in septal neurons in vitro. Studies performed in vivo show that IL-1 administration

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79

TABLE 8. Effects of cytokines on the thyroid gland a. In Vivo Cytokine

Species

Administration

IL-1/3

Rat

sc

IL-1/3

Rat

Minipump

IL-1/3

Rat

IL-1 IL-la

Mouse Mouse

Continuous infusion into CSF Continuous sc infusion Continuous 7 days

TNFa

Rat

iv, 1 or several

TNFa

Rat

Continuous infusion, ip minipump

TNFa TNFa

Mouse Human

ip 3 days iv

Effect

Ref.

4 Total serum T4 and T3; | free T4 due to 4 secretion, not to j catabolism 4 Free T4 (first 2-4 days), 1 plasma total T4 and T4 binding the whole week. Depending on dose, 4 plasma TSH, impaired TSH responsiveness to TRH 4 Plasma T4, TSH only 4 after 7 days By 24 h, 4 proTRH mRNA in PVN 4 Serum T4 and T3 4 Serum T4 due to inhibition of release, thyroid in vitro unresponsive to TSH, f pituitary TSH 22 and 31 days after treatment 4 Serum TSH, T4, free T4, T3 and hypothalamic TRH pituitary TSH/3 mRNA, thyroid 125I uptake and T 4 and T3 release in response to TSH, no change in TSH response to TRH 4 T4, 4 binding of T4 in plasma caused by reduction of T4-binding prealbumin, no effect on basal or TRH-stimulated TSH levels. 4 rT3, | T3/T4 ratio, 4 T3 and T4 responses to TSH 4 T 3 and TSH, | rT3, T4 and free T4 not affected

372 323 373 374 375 334

376 377 378

b. In Vitro Cytokine

Species

Effect

Ref.

IL-1/3 IL-1/3 IL-la,/3 IL-la,/3 IL-la,/3

Rat thyroid cell culture Human, normal, and thyrocytes Graves' Human, thyrocytes Graves' Human thyroid cell culture Human thyrocytes

4 f 4 4 4

Growth or 4 TSH-induced TRG release (dose-dependent) TSH-induced TRG release TRG secretion and cAMP 125 I incorporation and iodothyronine release

379 380 381 379 382

IL-6 IL-6

Human thyrocytes Human thyrocytes Graves'

No effect 4 TSH-induced T 3 secretion and thyroid peroxidase mRNA

383 384

TNFa TNFa

Human thyrocytes Human

4 125I incorporation and iodothyronine release Blunted TSH-induced TRG release

382

IFNy

Human, thyrocytes normal and Graves'

386

IFNy

Human thyrocytes

4 TSH-stimulated human TSH receptor gene expression 4 125I incorporation and iodothyronine release

385

382

CSF, cerebrospinal fluid; sc, subcutaneous; TRG, thyroglobulin.

stimulates neurons of the paraventricular and supraoptic nucleus of the hypothalamus as well as neurons of the stria terminalis. IL-2 and IFN7 stimulate neuronal activity in the cortex and hippocampus. In contrast, IL-1 and IL-6 exert an inhibitory action on neurons of the anterior hypothalamus. In brain slices, IL-1 stimulates neurons of the supraoptic nucleus of the hypothalamus, an effect that is modulated by y-aminobutyric acid (GABA)-ergic inputs. This cytokine inhibits long-term potentiation in the hippocampus and decreases voltage-gated calcium currents in dissociated CA1 neurons. TNF and IFN7 also inhibit long term potentiation. IFN7 exerts an excitatory effect in CA3 pyramidal cells and decreases evoked inhibitory potential amplitude. TNF stimulates neurons of the organum vasculosum of the lamina terminalis. c. Effect of immune-derived

products on peripheral nerve

activity. Another way through which neuro-endocrine structures could receive information from the immune system is the action of immune-derived products on peripheral nerve fibers. Although the effects of cytokines on peripheral nerves

have not been explored as widely as those on the CNS, some data are available. SP increases markedly in cultures of superior cervical ganglia grown in the presence of conditioned medium from concanavalin A-stimulated splenocytes. The effect is mimicked by IL-1, does not involve nerve growth factor, and seems to be somewhat specific since the activities of tyrosine hydroxylase and tryptophan hydroxylase are not altered (449,450). IL-1 does not act directly upon neurons to raise SP, but rather through the induction of leukemia inhibitory factor (451). It has also been shown in vitro that IL-1 suppresses the evoked NA release from rat myenteric nerves (452). The in vivo evidence that administration of cytokines affects peripheral nerve activity does not indicate whether the effect is primarily exerted at peripheral or central levels. For example, systemic administration of IL-1 increases the rate of firing of splenic nerve fibers (453). Intraperitoneal injection of IL-1/3 into rats also produces an increase in NA levels in the spleen, as determined by in vivo microdialysis (454), and accelerates NA turnover in the spleen, lung, diaphragm, and

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Vol. 17, No. 1

TABLE 9. Effect of cytokines on CNS neurotransmitters and central neuronal activity a. In Vivo Cytokine

Effect

Ref.

I NE in Hy and BS; f MHPG/NE forebrain, BS, and spinal cord; t Trp in all brain regions and in the cervical spinal cord 4 NE and E; | MHPG in Hy, | HVA in Str and Hy medulla; MHPG and NE changes in Hy blocked by indomethacin Push-pull to infuse and collect, medial basal Hy, f DA and DOPAC Microdialysis to inject and collect into AHy, t release of NE, DA, 5-HT, MHPG, DOPAC, HVA, and 5-HIAA Microdialysis in Hip, intraHip administration, f 5-HT icv; T extracellular 5-HIAA in anterior Hy 1 Cerebral concentration MHPG (largest in Hy, medial division); f Trp throughout the brain ip; t MHPG, 5-HIAA and Trp, but not DOPAC f NE turnover in Hy and Hip, f 5-HT turnover in Hip and prefrontal Cx; f DA utilization in prefrontal Cx icv, c-fos mRNA in Hy and immunoreactivity in PE, PVN, SON, ARC, SuM Lateral ventricle, blocks spontaneous expression of c-fos protein in the nucleus of LH-RH neurons between 1730 and 1800 h on proestrus. iv; I immediate-early gene c-fos expression in CRF and oxytocin-producing cells of the PVH. Also cell groups in bed nucleus of the stria terminalis, the central nucleus of the amygdala, the lateral parabrachial nucleus, and the dorsomedial and ventrolateral medulla iv; f electrical activity of single neurons in the PVN No alterations in MUA discharge of POA/AH but 4 EEG synchronization iv; i MUA in lateral margin of AHy iontophoretically or by micropressure into bed nucleus of stria terminalis, single unit extracellular recording; marked excitations of long duration I NE turnover in Hy and DA turnover in prefrontal Cx, but not 5-HT icv; I neuronal Cx and Hip activity t 5-HT and DA activity in Hip and prefrontal Cx, but does not affect central NE activity Microiontophoretic application, t single cell neuron activity in Cx and Hip

417

Species

IL-1/3

Rat

IL-1

Rat

IL-1/3 IL-1/3

Rat Rat

IL-1/3 IL-1/3 IL-la,/3

Rat Rat Mouse

IL-la,/3 IL-1/3

Mouse Mouse

IL-la IL-1/3

Rat Rat

IL-1

Rat

IL-1/3 IL-1/3 IL-1/3 IL-1/3

Rat Rat Mouse Rat

IL-2 IL-2 IL-6

Mouse Rat Mouse

IFNy

Rat

418 419 421 316 420 422 423 424 425 324 426

427 428 26 429 424 431 424 432

b. In Vitro Cytokine

Species

Effect

Ref.

In Cx synaptic preparations, | GABAA receptor function Hy, f release of NE and DA Hy slices, | release of monoamines Brain slices; f firing of in 60% neurosecretory neurons in the SON (intracellular recordings) f And prolonged synaptic inhibition (intracellular recording of hippocampal pyramidal cells of the CA1 region) Depolarizes membrane potentials in most SON neurons Local GABAergic inputs modulate IL-induced excitatory responses (intracellular recordings in slices) 4 voltage-gated Ca 2+ current in acutely dissociated hippocampal CA1 neurons (whole-cell patch clamp) Hip slices, | LTP of the slope of the population excitatory postsynaptic potential and the population spike amplitude in CA1 Hip slices, 4 K-evoked, but not the basal, release of ACh Embryonic primary septal neurons, | ChAT activity Isolated median eminence, | stimulation-evoked release of NE from noradrenergic axon terminals. No effect on spleen NA release. Hip slices; extracellular recording, Cal region from stratum pyramidale and stratum radiatum, f basal neurotransmission, f LTP after long lasting application Slices; extracellular single-unit recordings, | firing rate 44% neurons in OVLT

433 434 421 435

IL-1/3 IL-1/3 IL-1/3 IL-1/3

Mouse Rat Rat Rat

IL-1/3

Rat

IL-1/3

Rat

IL-/3

Guinea pig

IL-1/3

Rat

IL-2 IL-3 TNFa

Rat Mouse Rat

TNFa

Rat

TNFa

Guinea pig

IFNy IFNy IFNy

Rat Rat Rat

Embryonic septal nuclei with adjacent basal forebrain, f ChAT activity and mRNA Hip slices, I STP, 4 LTP Hip slices; excitatory effect on CA3 pyramidal cells and 4 evoked inhibitory postsynaptic potential amplitude

444 445 446

G-CSF GM-CSF

Mouse Mouse

Embryonic primary septal neurons, | ChAT activity Embryonic primary septal neurons, f ChAT activity

440 440

436 437 438 439 52 440 441 442 443

ACh, Acetylcholine; ChAT, choline acetyltransferase; Trp, tryptophan; HVA, homovanillic acid; NE, norepinephrine; DA, dopamine; 5-HT, 5-hydroxytryptamine; MHPG, 3-methoxy 4-hydroxy-phenylglycol; DOPAC, 3,4-dihydroxyphenylacetic acid; 5-HIAA, 5-hydroxyindole-3-acetic acid; GABAA, gamma-aminobutyric acidA; Hy, hypothalamus; Hip, hippocampus; Str, striatum; BS, brain stem; POA, preoptic area; AHy, anterior hypothalamus; MUA, multiunit activity; EEG, electroencephalogram; Cx, cortex; OVLT, organum vasculosum lamina terminalis; LTP, long term potentiation; STP, short term potentiation; PE, periventricular; PVN, paraventricular nucleus; SON, supraoptic nucleus; ARC, arcuate nucleus; SuM, supramammillary nucleus; f , stimulate or increase; 4 , decrease or inhibit.

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81

pancreas without appreciable effects in other organs (455). profound effects on behavior, e.g. learning and explorative IL-6 does not affect NA turnover. Thus, while both cytokines and avoidance behavior (476,477). Some of these actions are are effective for adrenocortical activation, only IL-1 increases likely to occur at CNS levels since intracerebroventricular administration of IL-lra blocks such effects (478). Cytokines sympathetic nerve activity (454, 455). However, since IL-1 may be involved in the central mechanisms for learning and administered intracerebroventricularly also induces an inmemory since IL-1, TNFa, and IFNy inhibit long-term pocrease in splenic NA turnover, the stimulation of the symtentiation, a mechanism that is thought to underlie these pathetic activity seems to be, at least in part, centrally meprocesses (464). diated (454-456). /. Effect of cytokines acting in the brain on peripheral immune Antigens trapped in the spleen and immune cells that functions. Cytokines acting on the CNS can affect immune cell home in this organ are derived from the circulation. Therefunctions. For example, intracerebroventricular infusion of fore, the blood flow of this organ plays an important role in IL-1 decreases cell-mediated immune responses, natural splenic immune functions. We have recently observed that killer cell activity, the response to mitogen, and IL-1 and IL-2 IL-1 causes an increase in splenic blood flow. This effect is production (308,479). Blockade of HP A axis stimulation and abrogated by surgical interruption of splenic nerve fibers of sympathetic nervous system activation by IL-1 not only (457). reverses these effects but also causes an increase in the proThere are indications that afferent neural pathways may duction of IL-1 by splenic macrophages (308, 479). mediate effects of cytokines on the brain. Vagotomy interferes with behavioral alterations that follow LPS adminis3. Metabolic effects of cytokines. It is quite obvious that because tration (458). The increases in brain tryptophan caused by of the variety of mechanisms involved, the activation of the intraperitoneal injection of endotoxin or IL-1 are prevented immune-neuro-endocrine network will have an impact on by pretreatment with the ganglionic blocker chlorisondamgeneral host homeostasis. Metabolic derangements occur ine. Thus, the autonomic nervous system appears to be inwhen the immune system is activated during inflammatory, volved in the IL-1-induced changes in brain tryptophan infective, and neoplastic processes (480-485). There is evi(459). d. Effect of cytokines on neuronal growth and differentiationdence and that such derangements are mediated, at least in part, by immune-derived cytokines such as IL-1 and TNF (486nerve repair. Cytokine-containing supernatants obtained 491). The effect of these cytokines is exerted either directly or from activated lymphocytes maintain sympathetic neurons in culture (460). IL-1, IL-6, IFNy, and TNFa stimulate pro- through their action on neuro-endocrine mechanisms. In this section, the effect of IL-1 on glucose metabolism is given as liferation of astroglial cells and neurons (461). The effects of an example of the capacity of an immune-derived product to IL-3 seem to be more specifically directed to neurons since affect a parameter which, under physiological conditions, is this cytokine preferentially stimulates neurite outgrowth of cholinergic neurons (462). IL-1 stimulates the activity of cho- under multifactorial regulation. Alterations in glucose blood levels are detected during the line acetyltranferase in cultures of sympathetic ganglia (463). course of certain pathological conditions in which IL-1 is IL-1 can also influence nerve cell growth since it induces the production of nerve growth factor in vitro (464). Additional known to be produced. Administration of nanogram details on the involvement of immune cytokines in the conamounts of IL-1/3 into mice of different strains results in trol of neuronal cell growth and differentiation and nerve decreased glucose blood levels. Insulin levels are increased repair under pathological and probably also during physi2- to 3-fold for about 4 h when IL-1 is injected into endotoxinological conditions can be found in specific reviews (465resistant C3H/HeJ mice. However, no changes in the levels 467). of this hormone were observed in parallel to the hypoglye. Effect of cytokines on thermoregidation, food intake, sleep,cemia and induced by IL-1 in three other strains of mice that are behavior. Immune cytokines influence complex mechanisms not endotoxin resistant. Functional tests for glucose tolerance that involve a variety of neuronal circuits such as thermowere performed in mice who had previously received single regulation, food intake, sleeping patterns, and behavior. As or repeated injections of IL-1 (487). This treatment results in stated in the introduction, these effects will not be discussed an accelerated glucose clearance. Furthermore, in spite of the in detail since recent reviews have been published. We shall administration of exogenous glucose, these animals develop mention here only a few examples. The notion of the exisa long lasting hypoglycemia. It appears therefore that the "set tence of an endogenous pyrogen is now fully established point" of the regulatory mechanisms that stabilize glucose with the exception that not one, but several, endogenous concentration in blood is adjusted to a lower level after IL-1 substances, such as IL-1, IL-6, IL-8, IFN7, IFN/3, and GM-CSF treatment (487). (468-470), possess the capacity of inducing fever. Also, sevIncreased adrenaline and glucocorticoid output from the eral cytokines inhibit food intake, among them IL-1, IL-6, adrenals is a major counterregulatory mechanism tending to IL-8, and TNFa (469, 471). The capacity of increasing slow normalize glucose blood levels during hypoglycemic states. wave sleep is also shared by different cytokines such as IL-1, Adrenalectomy abrogates these mechanisms and results in IL-2, IFN7, and TNFa (472, 473). A dual role of cytokines in reduced glucose production. When IL-1 is administered to the sensitivity to pain has been described. IL-1 and IL-6, adrenalectomized animals, the hypoglycemia thus induced acting at sites of inflammation, sensitize afferent fibers by is more pronounced than in normal mice and is paralleled by stimulating the release of prostaglandins (474). However, a marked reduction in insulin blood levels. Thus, there is a when IL-1 is given systemically, it mediates an antinocicepdissociation between insulin and glucose levels in adrenative response (475). Several cytokines are known to exert lectomized mice that received IL-1. These data, taken to-

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gether with the results mentioned above, suggest that IL-1induced hypoglycemia cannot be explained by an insulin secretagogue action of this cytokine. Therefore, it is possible that IL-1 is involved in the increased non-insulin-mediated glucose uptake observed during sepsis (492). This led us to study the effect of IL-1 in two mouse strains that are models of insulin-resistant diabetes. Genetically diabetic C57B1/Ks db/db and C57B1/6J Ibm ob/ob mice are both hyperglycemic and markedly hyperinsulinemic; furthermore, they have fewer insulin receptors and are resistant to the exogenous administration of insulin. We found that IL-1 also acts as a hypoglycemic agent in this type of diabetic animal (493). Interestingly, it has been recently reported that TNF expression is increased in these animals and that this cytokine induces insulin resistance (494, 495). In normal rats, the hypoglycemic effect of IL-1/3 is modest. A likely mechanism that could explain this is the reduction in insulin levels observed in rats after IL-1 administration (487, 496) that occurs in parallel to the release of glucocorticoids and catecholamines. Although other authors, using another source of the cytokine, have reported that IL-1/3 induces hyperinsulinemia in normal rats (497), all reports agree that this cytokine induces a marked hypoglycemia and a profound decrease in insulin levels in adrenalectomized rats (487, 498). It has been reported that, in contrast to mice (487), repetitive injections of IL-1 to rats cause a degree of glucose intolerance (499). This can also be explained by both the reduction in insulin release and the effect of counterregulatory hormones. It is, however, noteworthy that IL-1 exerts more profound effects in insulin-resistant Zucker fa/fa rats than in control rats since it normalizes several metabolic parameters, including glucose tolerance (500). Several mechanisms seem to contribute to IL-1-induced hypoglycemia (501). It was reported that IL-1 inhibits glucocorticoid-induced hepatic gluconeogenic enzymes (502) and stimulates glucose transport in adipocytes and fibroblasts (503, 504). These results agree with a previous report showing that a macrophage-derived factor causes increased glucose transport and oxidation (505). Central mechanisms also seem to participate in mediating the hypoglycemic effect of IL-1. Intracerebroventricular injection of the cytokine induces hypoglycemia (506), and glucose-sensitive neurons in the ventromedial hypothalamus are affected by this cytokine (507). As previously mentioned, the effect of IL-1 on glucose metabolism is only one example of how an immunologically derived product can affect essential processes related to general homeostasis. Other lymphomonokines, such as TNF, can also affect general metabolism (490).

III. Immune-Neuro-Endocrine Circuits Most of the information discussed so far derives from studies based on pharmacological or surgical manipulations of neuro-endocrine mechanisms and on administration of immune-derived products. These studies suggest that there may be a tonic control of the immune system by hormones, neurotransmitters, and neuropeptides, on the one hand, and

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that immune-derived products, such as cytokines, can affect neuro-endocrine mechanisms, on the other. However, the regulation of any physiological system is based on dynamic interactions between the physiological variable and regulatory systems. Thus, we have proposed and provided experimental evidence showing that neuro-endocrine responses mediated by immune-derived products are elicited after activation of the immune system (281, 279). Such responses indicate the operation of a network of interactions between immune-derived signals and hormones, neurotransmitters, and neuropeptides. Moreover, the operation of this network is of importance for immunoregulation, host defenses, and homeostasis. The examples that we shall discuss in the following are classified either as long loop or as local interactions. Long loop interactions refer to processes in which the stimulation of the immune system results in the release of immune-derived mediators that can, in turn, affect distant neuro-endocrine structures. In contrast, local interactions are those in which both immunologically derived and neuroendocrine agents exert reciprocal effects within the tissue or organ where they are released. This classification is to some extent arbitrary, since, for example, it is possible that interactions occurring initially at a local level, either within a peripheral tissue or within the brain, could subsequently affect distant neuro-endocrine mechanisms. A schematic representation of immune-neuro-endocrine networks is shown in Fig. 2. A. Long loop immune-neuro-endocrine circuits

As mentioned, there is abundant evidence that neuroendocrine and metabolic alterations parallel infective, inflammatory, autoimmune, and neoplastic diseases. These alterations could be directly caused by the infective agent or neoplastic cells and/or their products, or by the tissue injury that they may induce, and be, therefore, the consequence of the disease. Alternatively, the changes in neuro-endocrine functions and intermediate metabolism observed during certain pathologies may be mediated by factors released when the immune system is activated. These changes may constitute part of host-mediated mechanisms that could, in turn, affect the operation of the immune system. The identification of which immune-derived factors are affecting neuro-endocrine and metabolic processes during a given disease, and whether they are ameliorating or aggravating its course, is of clinical relevance. Thus, immunologically mediated neuroendocrine responses may be beneficial for the host, but, under certain circumstances, they might become detrimental (see discussion below). Several strategies have been used to distinguish between neuro-endocrine effects related to the activation of the immune system itself and those that are consequences of the disease. Although other strategies may still be proposed, the following is a list of those for which examples are available: 1. To trigger immune responses with innocuous, noninfective, nonneoplastic antigens and to search for changes in endocrine, central, and peripheral neural activity occurring subsequent to the activation of the immune system. 2. To show that direct contact of immunological cells with disease-causing agents, in which neuro-endocrine alterations

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IMMUNE-NEURO-ENDOCRINE INTERACTIONS

Psycho-sensorial Stimuli

Behaviour

CNS

Immune and Neuroendocrine Products

Endocrine System (Hormones)

and Immune Cell Products

Peripheral Nervous System (Neurotransm. Neuropeptides)

Immune and Neuroendocrine Products

IMMUNE SYSTEM

Antigenic Stimuli

Immune Response

FIG. 2 The CNS and the immune system exchange information using hormones, neurotransmitters, neuropeptides, and immune cell-derived products as mediators. The box representing the immune system includes not only the classic immunological organs, but also all peripheral tissues where an immune response may take place. The endocrine and the peripheral nervous systems are represented together because of their multiple interconnections. When the exchange of signals occurs between immune and neuro-endocrine structures that are distant from each other, a long-loop circuit is established. When immune-neuro-endocrine communication is based on exchange of paracrine signals, either at peripheral or at central levels, local interactions are established (circles within boxes). Long-loop circuits and local interactions are also interconnected. The degree of activity of the immune-neuro-endocrine network can be affected at the level of the immune system, after internal or external antigenic challenge, or at the level of the CNS, by sensorial and psychosocial stimuli. The branching out arrows symbolize the consequences of interactions between immune, endocrine and nervous systems for the whole organism.

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are observed, induces the production of mediators capable of eliciting similar neuro-endocrine changes in healthy individuals. 3. To confirm that neuro-endocrine alterations occurring during diseases that involve the immune system are not expressed in individuals lacking the particular type of immunological cells involved. 4. To establish that neuro-endocrine changes that follow administration of infective and neoplastic agents that stimulate the immune system are detectable before the overt onset of the disease. In the following, we provide information about long loop immune-neuro-endocrine interactions with particular reference to our own work. In this context, probably the most extensively studied circuit is the one based on the capacity of the immune system to affect the activity of the pituitaryadrenal axis. Increased glucocorticoid blood levels have been observed during the course of specific immune responses to different innocuous antigens (202, 280, 508, 509). These changes are only detected when the immune responses are intense enough to reach a given threshold. For example, when the Biozzi high-low responder strain of mice is used, significant increases in corticosterone blood levels are observed only in immunologically high responder animals (510). It has been argued that the magnitude of the effect of specific immunization on the pituitary-adrenal axis is modest when compared with that observed after acute administration of individual cytokines (511). In our view, these effects cannot be compared, since immunization causes, in a threshold-dependent manner, a 3- to 4-fold increase in glucocorticoid blood levels that is sustained over several days. In contrast, a bolus injection of certain cytokines, such as IL-1, results in stimulation of the HPA axis to a more marked degree, also depending on the dose administered, but lasting for a few hours only. Profound increases in ACTH and corticosterone blood levels are also observed after mice are inoculated with Newcastle disease virus (NDV), a virus that produces a mild disease in rodents (282, 289, 512). Two hours after injection of this virus, the levels of ACTH and corticosterone in blood are already increased several fold. This effect is not caused by the virus itself or by the stress of the infection but by the release of lymphokines or monokines from immunological cells. It was shown that IL-1 is the main cytokine involved in stimulation of the HPA axis after administration of the virus. These studies provided the first evidence that IL-1 can mediate the increase in glucocorticoid levels after the administration of a natural infective agent (282). It has been known for a long time that bacterial endotoxins can stimulate the pituitary-adrenal axis. This increase in glucocorticoid levels has protective effects during septic shock (513). More recently it has been shown that endotoxin stimulation of the pituitary-adrenal axis is caused by products from activated macrophages (514) and that IL-1 is the main mediator of this effect (290). An early increase in glucocorticoid blood levels is also observed after syngeneic tumor transplantation (515). In at least one model, this effect is mediated by factors derived from immunological cells (516-518). A biphasic increase in glucocorticoid levels is observed after administration of EL-4

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lymphoma cells. The early 8- to 10-fold increase in corticosterone blood levels occurs within 24 h after tumor cell transplantation, well before the tumor becomes detectable. The presence of T cells is required to elicit such changes in glucocorticoid levels. Furthermore, a host-derived factor present in the ascitic fluid of animals bearing an EL-4 lymphoma stimulates the pituitary-adrenal axis upon transference to a normal host (516, 518). Not all types of immune responses result in stimulation of the pituitary-adrenal axis. During skin graft rejection, corticosterone blood levels are lower than in animals bearing autografts (519). A more recent report showed that major alterations in the processing of POMC in the pituitary gland are observed during skin graft rejection (520). Several other endocrine processes are affected during the course of activation of the immune system. Reduced levels of circulating thyroid hormones during the immune response to innocuous antigens such as sheep red blood cells (SRBC) and trinitrophenylated-hemocyanin have been reported (280). This finding may explain the inhibition of thyroid function that is observed during infective diseases (521). Early increases in PRL blood levels occur after administration of Freund's complete adjuvant to rats (522). Inoculation of 1 X 106 cells from methylcholantrene- or dimethylbenzantracene-induced tumors, but not of normal cells, causes a clear increase in PRL and corticosterone and a decrease in T4, insulin, and testosterone blood levels after 24-48 h (515). These endocrine changes precede the overt appearance of the tumor by several days, and there is a lack of correlation between the progression of the tumor and the majority of the endocrine alterations observed. This fact suggests that these hormonal changes are not directly mediated by tumor cell products but rather constitute a host response to endogenously induced mediators capable of affecting neuro-endocrine mechanisms. The autonomic nervous system is also affected during activation of the immune system. The NA content in lymphoid organs of animals bred under conventional conditions is lower than in those of immunologically less active, germfree animals (523). We have also observed decreased sympathetic activity in the spleen during the immune response, as evaluated by the NA content and turnover rates (195,524, 525). Administration of Freund's complete adjuvant induces a decrease in the total content of NA in the spleen that lasts several days (526). These findings indicate that sympathetic activity is reduced during certain immune responses. However, other authors have shown that, after inoculation of Freund's complete adjuvant into rats, the sympathetic and cholinergic nerve activity in submaxillary lymph nodes is increased (527). As it will be discussed in Section B below, interactions between the autonomic nervous system and immune mechanisms are difficult to classify as long loop or as local immune-neuro-endocrine interactions. From the data concerning endocrine and autonomic responses during activation of the immune system, it cannot be concluded that the CNS is directly involved in all of the peripheral effects discussed above. However, the observed changes in the endocrine and autonomic nervous systems reflect, if only indirectly, the existence of afferent pathways in immune-brain communication. Since the hypothalamus inte-

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grates most endocrine and autonomic functions, the possibility that hypothalamic neurons receive signals derived from the immune system was explored. It was shown that after inoculation of SRBC or trinitrophenylated-hemocyanin, the frequency of firing of neurons in the ventromedial nucleus of the hypothalamus is increased several fold at a time close to the peak of the immune response (528). No statistically significant changes were detected at the time of the peak immune response to SRBC in the arcuate, premamillaris dorsalis, and paraventricular nuclei and in the pre-optic, anterior, and posterior areas of the hypothalamus, and in the reuniens thalamic nucleus (200). The results of these experiments, which were performed in anesthetized rats, show that the hypothalamic response does not involve general neuronal activation after antigenic challenge. In fact, they suggest that the information derived from activated immune cells follows specific pathways. Neuronal multiunit activity was also studied in the hypothalamus of freely moving, conscious rats using chronically attached recording electrodes. Changes in the rate of firing of neurons of the paraventricular hypothalamic nucleus and in the anterior hypothalamic area were detected after immunization with SRBC (529). The hypothalamus is subject to hormonal feedback signals. Therefore, it cannot be decided whether a change in the electrical activity of hypothalamic neurons is causally related to the reception of immune messages or to the emission of endocrine signals. Furthermore, some hypothalamic neurons are influenced by neurotransmitters that are derived from neurons that follow anatomically well identified pathways, connecting the hypothalamus with distant parts of the brain. Aminergic neurons projecting to the hypothalamus are important regulators of hypothalamic neuronal activity. On this basis, catecholamine turnover rates in different regions of the CNS during the immune response to SRBC were studied (279). In immunologically, high-responder rats, a marked decrease in hypothalamic NA turnover rate compared with salineinjected controls was noted 4 days after antigen administration, whereas immunologically, low-responder animals had turnover rates almost equal to those of the controls. This effect seems to be specific since no changes in dopamine turnover in the CNS were observed during the immune response. Other authors have shown that, during the immune response to SRBC, the NA content is markedly reduced in the paraventricular nucleus of the hypothalamus (530). This effect of immune stimulation on the CNS may explain the changes in NA content of the hypothalamus that have been observed after inoculation of Newcastle disease virus (512). In addition, the administration of muramyl dipeptide, which is cleaved from membrane walls of gram-negative bacteria and induces several cytokines, was shown to cause a reduction of serotonin metabolism in the CNS (531). The endocrine and autonomic changes and the changes in electrical activity and turnover rate of catecholamines in the brain after activation of the immune system constitute clear evidence of the reception of immune-derived signals by the CNS.

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IMMUNE-NEURO-ENDOCRINE INTERACTIONS

B. Immune-neuro-endocrine circuits operating at local levels

All tissues, including those from the so-called immune privileged organs, contain resident immune cells. During certain pathological conditions, resident cells of the macrophage lineage become activated, and one of their main functions is to provide adequate antigenic presentation to lymphoid cells that are either already in the tissue or are derived from the circulation. These events, which lead to specific immune responses, occur in parallel to the recruitment, in a particular sequence, of other types of leukocytes that are involved in nonspecific immunity and inflammatory processes. These cells and their products coexist with hormones reaching the interstitial space as well as other substances, including biogenic amines and neuropeptides such as SOM, SP, and VIP, which are locally produced by the diffuse neuroendocrine system (532,533). Peptide hormones generated by immune cells might be also present. Mucosa and epithelium are the interface with the external milieu. In these tissues, products from immune and neuro-endocrine cells and antigens interact most intensively, particularly since they possess lymphoid aggregates that are in contact with the local flora, such as the Peyer patches in the gut (534). Specialized primary and secondary lymphoid organs, apart from being the organs in which immune cells develop, are also potential sites of immune-neuro-endocrine interactions. As mentioned before, these organs are extensively innervated by autonomic and peptidergic fibers. Furthermore, local production of peptides such as vasopressin, oxytocin, and VIP, as well as steroid hormones, have been detected in the thymus (237, 238, 535). As mentioned in previous sections, there is evidence that cytokines can affect the activity of peripheral nerves and that certain neurotransmitters and neuropeptides can influence cytokine production. Even antibodies are potential mediators of peripheral immune-neural interactions since the Fc part of immunoglobulins can bind to peripheral nerve fibers in normal animals (536). Local immune-neuro-endocrine interactions can also be established in the CNS since, as mentioned above, several cytokines can be produced by both glial and neuronal cells, implying the coexistence of these mediators with neurotransmitters and neuropeptides in the brain. Furthermore, there is evidence that activated T cells can cross the blood-brain barrier and migrate into the CNS (537, 538). These cells may establish local immune-neuro-endocrine interactions in the CNS through the local release of cytokines that can affect the activity of neural cells. When this information is compiled, there is anatomical, biochemical and pharmacological evidence suggesting that functional immune-neuro-endocrine interactions can occur at local levels. However, these functional interactions are difficult to detect because they are assumed to occur in a paracrine fashion and in restricted areas of specialized tissues. Furthermore, it is difficult to establish whether the effect of an immune process is not the consequence of nonimmunological stimuli that parallel a given disease. For example, the production of sensory peptides in sites of inflammatory or local immune processes may not necessarily be induced by interactions between immune cell products and nerve fibers. Alternatively, they might reflect the conse-

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quence of nociceptive and mechanical stimuli generated during inflammatory processes. These difficulties probably explain why there are not many examples of functional immune-neuro-endocrine interactions locally within a given tissue. However, some clues for such interactions can be mentioned. Axonal reflex mechanisms contribute to the vascular and cellular components of localized inflammatory and immune processes. Some cytokines may stimulate these mechanisms since, through induction of prostaglandins, they sensitize afferent nerve fibers (474). There is also evidence that this reflex can be initiated by mast cell products (539). Consequently, sensory peptides, like SP and neurokinin A, are released; these can induce the production of the proinflammatory cytokine IL-1 and the expression of IL-2 receptors in gut-associated lymphoid tissues (266). Furthermore, as mentioned above, some neuropeptides can affect mononuclear cell mobility. As a whole, these observations suggest the existence of a local circuit involving immune cell products and neural mechanisms. A further example can be derived from experiments showing that the altered function of enteric nerves in a model of intestinal inflammation in nematode-infected rats is mediated by endogenous IL-1. The cytokine is most likely released by macrophage-like cells in the myenteric plexus. In turn, this cytokine-induced change in neurotransmitter content and release is expected to affect immune cell functions, thus establishing a neuroimmune circuit in the myenteric plexus (452, 540). A further example is the finding that, after instillation of food antigens in the rat intestine, a cholinergic mechanism mediates an increase in the release of IgA and IgG antibodies (541). However, the immunological mediation of this phenomenon needs further clarification. As mentioned in the previous section, our studies and those of others concerning changes in the activity of sympathetic nerves during activation of the immune system are at present difficult to classify as local or long loop interactions. For example, the NA content in lymphoid organs of animals bred under conventional conditions is lower than in lymphoid organs of germ-free rats, in which immunological stimulation by environmental antigens is markedly reduced (523). This may indicate that immune-derived products affect sympathetic nerve activity in the lymphoid organs where they are produced. These interactions would then be considered as occurring at a local level. However, and in contrast to the other nonlymphoid organs studied, the NA content of the adrenal gland is also decreased in the immunologically more active rats. This indicates that an organ distant from the main site of cytokine production is also affected, and, in this case, immune-sympathetic interactions would be considered as part of a long loop. Local circuits could also be established during development, as illustrated by studies on the innervation of the spleen in nude mice. These animals have a hyperinnervated spleen as evaluated by histochemistry and by the NA content. When T lymphocytes, the cells these animals lack, are injected or a thymus is implanted at birth, there is a reduction in sympathetic fibers and in the content of the neurotransmitter in the organ (542). Therefore, T lymphocytes, which in normal animals are in close contact with sympathetic fibers, seem to provide a stop signal for the growth of the neural

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and IFNy, specifically protect T helper cells from the inhibitory effects of glucocorticoids (553-555). As the immune response proceeds, the stimulation of the HPA axis will result in inhibition of the production of certain lymphokines and/or monokines (250-254). In this way, the increase in glucocorticoid levels induced by the immune response will affect already activated cells with high affinity for the antigen less than accessory cells or resting or low affinity lymphocytes. This is reflected by the phenomenon of sequential antigenic competition. The levels of corticosteroids in blood that are attained at the peak of the immune response to an antigen inhibit the response to other unrelated antigens administered at this time. Such competition is, to a large extent, abrogated by adrenalectomy or hypophysectomy (551,556). On this basis, we have postulated that the regulatory function of the immune-HPA axis circuit is to prevent an inappropriate, excessive expansion and activity of immunological cells and overproduction of lymphokines and C. Relevance of immune-neuro-endocrine circuits for monokines. immunoregulation There are other examples of the potential discriminatory In Section II.C, we gave examples showing that hormones, effects of neuro-endocrine signals that act predominantly on neurotransmitters, and neuropeptides can affect defined activated immune cells. After activation, lymphocytes exsteps and processes of the complex sequence of events that press more receptors for certain hormones and neurotranslead to a specific immune response. However, neuro-endomitters. As previously mentioned, resting lymphocytes have crine mechanisms that contribute to immunoregulation no detectable receptors for insulin, whereas they are present should not interfere with, and even preserve, immunospeciafter stimulation (3, 4, 557). Muscarinic and j3-adrenergic ficity. Such a contribution could be based on a differential receptors also increase after activation of lymphoid cells (22, sensitivity of immune cells to neuro-endocrine agents, which 23). Thus, it is predominantly those cells activated by the may depend on the state of activation of these cells after antigen that will perceive hormonal or neurotransmitter antigenic challenge. This implies that, to be efficient, a neuro- signals. endocrine response should occur at a defined step of the The particular location of immunological cells during the immune process. This is clearly illustrated by the immuneimmune response could also determine the selective neural HPA axis circuit. effects on antigen-stimulated lymphocytes. The immune reGlucocorticoids have antiinflammatory effects, and they sponse develops in well defined anatomical structures. After can act as immunosuppressive agents. However, there is also immunization of rats with SRBC, B cells producing specific evidence that glucocorticoids can stimulate certain immune antibodies appear first in the white pulp of the spleen close mechanisms. These dual effects of glucocorticoids on the to the periarteriolar sheath (558). This location, which is a T immune system have been extensively reviewed (168, 169, cell-dependent area, is optimal for T-B cell interactions. The 545). In the following, some of the effects of glucocorticoids release of NA by sympathetic nerves in the spleen is prethat would indicate the relevance of the immune-HPA axis dominantly restricted to the same zone (64, 65). Therefore, circuit for immunoregulation are briefly discussed. antigen-activated B cells would be more influenced than It is well known that the immunosuppressive effect of other B cells by sympathetic signals because of their location glucocorticoids on immune responses is maximally exerted in an splenic area with the highest NA content. Furthermore, when the hormone is given before immunization (546, 547). they would be more affected by the phasic changes in splenic This effect is less pronounced if the same dose is adminisNA content that are observed during the immune response tered during the course of the immune response because to SRBC (195). This decrease in NA content in lymphoid resting B and T lymphocytes are more sensitive to glucocor- organs would result in increased blood flow, and, therefore, ticoids than activated ones (548,549). Furthermore, antibody influence immune cell traffic. Since resting and activated synthesis by activated B cells can be stimulated by glucocor- lymphocytes display different homing and migratory patticoids (550, 551). Also, processes essential for the developterns, the neurally-mediated change in blood flow in imment of an immune response, such as antigen presentation mune organs is expected to contribute to immunoregulation and cytokine production, are glucocorticoid-sensitive (552). (559). The increase in glucocorticoid levels during an immune reAs described in parts A and B of this section, there are sponse is a late phenomenon. It is, therefore, expected that examples of activation of the immune system by innocuous this endocrine change would not significatively interfere antigens leading to the operation of immune-neuro-endowith antigen presentation, clonal expansion of activated lymcrine circuits. However, under natural conditions, the actiphocytes, and the initial production of immunoregulatory vation of the immune system is often linked to pathological cytokines. In this respect, it is noteworthy that IL-1, IL-2, IL-4, situations during which immune-neuro-endocrine circuits and another factor present in supernatants of mitogen-stimcoexist with host mechanisms that are also affected as a ulated spleen cells and distinguishable from IL-1, IL-2, IL-3, consequence of the disease. The following discussion will

fibers. This might explain why mice that develop strong autoimmune processes and have a hyperactive immune system, such as MRL-lpr/lpr mice, show a progressive loss of noradrenergic fibers in the spleen that correlates with the progression of the disease (543). These findings, together with the fact that splenic sympathetic innervation affects the immune response, would indicate that bidirectional interactions between T cells and nerve fibers occur in the spleen. It has been shown that experimental autoimmune encephalomyelitis is less severe when noradrenergic neurons in the CNS have been destroyed (544). This finding suggests that local immune processes in the brain can be influenced by these neurons. This, together with the evidence that cytokines can affect the activity of noradrenergic neurons (417, 418, 421-423), may serve as an example of local immuneneural interactions at CNS levels.

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k

1



* 4

•* t

IMMUNE-NEURO-ENDOCRINE INTERACTIONS

provide an example of the operation of these circuits during pathological conditions. The best characterized circuit is based on interactions between the immune system and the HPA axis. There is reasonable proof that normal bidirectional communication between these two systems can play a protective role whereas disruption of this communication can lead to predisposition to or aggravation of the disease. It is known that glucocorticoids in blood reach very high levels during sepsis. This increase is protective for the host since administration of sublethal doses of endotoxins such as LPS into adrenalectomized animals results in high mortality. It is now known that, in this model of sepsis, the stimulatory effect of LPS on glucocorticoid output is mediated by cytokines released by macrophages (514), most likely IL-1 (290). Cytokines, which stimulate the pituitary-adrenal axis, mediate the inhibition of the inflammatory reaction that is observed soon after tumor cell inoculation. One example is the previously described effect of injection of EL-4 lymphoma cells (516). Twenty four hours after injection of these cells, inhibition of the inflammatory reaction occurs in parallel to the immune cell-mediated increase in glucocorticoid blood levels. This antiinflammatory effect is not observed in adrenalectomized animals. Another example of this modulatory action of the pituitaryadrenal axis is observed in Lew/N female rats, which are susceptible to experimentally induced arthritis. These rats have a defective HPA axis that is poorly stimulated by cytokines such as IL-1 (560). A clinical correlate is the disturbed HPA axis of patients with rheumatoid arthritis (561). As mentioned above, the immune-HPA axis circuit may contribute to impede an excessive cumulative expansion of immune cell mass and activity. Disturbances in this circuit may contribute to the expression of lymphoproliferative and autoimmune diseases in genetically predisposed individuals, especially since these pathological events are the product of multiple factors that progressively disrupt immune cell homeostasis. In support of this view is the finding that Obese Strain (OS) chickens with spontaneous autoimmune thyroiditis do not respond to immunization with sheep erythrocytes with any detectable elevation in circulating corticosterone, which is in contrast to normal chickens (508, 545). OS chickens are capable of producing a factor that increases glucocorticoid blood levels upon injection into normal animals. The main cytokine responsible for this effect has been identified as IL-1 (562). However, OS chickens show a significantly reduced glucocorticoid response to the injection of this factor. A disturbed immune-HPA axis communication has also been found in murine models of lupus. After injection of IL-1, lupus-prone mice may reach nearly the same levels of plasma corticosterone as normal mice. However, since animals that will develop the autoimmune disease have higher baseline levels of plasma corticosterone, the increase in the concentration of this hormone was significantly lower than that of normal mice (563). Another example of the relevance of the immune-HPA axis circuit in the prevention or moderation of autoimmune diseases derives from studies on experimental allergic encephalomyelitis (EAE). Before and during the overt clinical expression of the disease, increased glucocorticoid levels are observed. Such increased levels help to mod-

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erate the clinical course of the disease since most adrenalectomized rats with EAE die during the first attack (564, 565). In summary, there are examples showing that immuneneuro-endocrine circuits participate in immunoregulation. This evidence does not contradict the fact that the immune system is also under control of very efficient autoregulatory mechanisms. In our view, mechanisms under CNS control would come into operation, depending on the intensity of the immune response and on the type of mediators released. If this is the case, the regulatory outcome will be the result of external neuro-endocrine signals and autoregulatory immunological mechanisms. Hormones, neurotransmitters, and neuropeptides could act directly on defined subsets of immunological cells, or they could synergize or antagonize the effect of immune system autoregulatory mechanisms.

IV. Homeostatic and Antihomeostatic Functions of the Immune System: Contribution to Natural Selection The preservation of a constant internal environment and the establishment of optimal interactions between different body constituents and the external world are the key features of homeostasis. The immune system contributes to homeostasis by recognizing and eliminating foreign and altered self-antigens, thus maintaining the appropriate cell types and molecules that constitute a tissue or organ at different stages of life. However, homeostasis, as a product of natural selection, contributes to evolution as long as the survival of one individual would not threaten the survival of other members of the species. In this sense, when referring to homeostasis mediated by the immune system, it is necessary to consider that an individual infected by pathogenic microorganisms may not only have his own life compromised but might also be a vector capable of transmitting this agent to another healthy individual. Therefore, there are conditions in which immune-mediated homeostasis enters into conflict with evolution. This would be the case, for example, when individuals who, although having a fully operative immune system, cannot deal, or deal ineffectively, with an infective agent. The longer the individual who carries a pathogen survives, the higher is the threat to the species. This conflict of interest between immune-mediated homeostasis and natural selection may be overcome by mechanisms referred to as "anti-homeostatic" functions of the immune system. Evidence is accumulating that stimulation of the immune system is, under certain conditions, detrimental and can lead to death of the individual. This is clearly shown in experimental models of sepsis. In such models, it would be easy to assume that the main cause of death is the neuro-endocrine and metabolic derangements induced by the invading microorganism or by its products, e.g. bacterial endotoxins. However, in recent years, as specific cytokine antagonists and blockers have become available, it has been shown that certain cytokines such as IL-1 and TNF, rather than products from the infective agent that causes the disease, me-

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diate these deleterious neuro-endocrine and metabolic derangements during sepsis. For example, administration of cytokine antagonists, specific antibodies, or soluble receptors protects animals from lethal effects of bacterial endotoxin (566-572). As mentioned before, LPS induces the production of cytokines that, by stimulating the HPA axis, cause a protective increase in glucocorticoid blood levels. However, with high doses of endotoxin, this protection is not sufficient and the levels of cytokines attained may result in the death of the animal. One might ask why there are not mechanisms efficient enough to impede the overexpression of genes whose products could cause self-destruction. A possible explanation is that these products may mediate processes of "active" negative self-selection, exerted by the immune system. These processes might have been acquired in evolution to limit homeostasis when the survival of the individual compromises the survival of other members of the species. Another way by which the immune system can contribute to evolution is through the association of immune and reproductive functions. As mentioned in Section D, some cytokines released during activation of the immune system interfere with the hypothalamus-gonadal axis (Table 5; Refs. 573-575). Although this is a speculative view, the inhibitory effect of these cytokines on reproductive functions may serve to impede the transmission of microorganisms to the progeny via the placenta or the milk. Another situation in which the association of immune and reproductive functions may lead to natural selection is observed when the development of the immune system is deficient. For example, nude mice (animals which genetically lack the thymus and therefore T lymphocytes) have profound alterations in sexual functions. These mice, as well as neonatal thymectomized mice, have a delay in puberty and an altered sexual cycle. These defects can be normalized by implantation of a thymus at birth. However, the alterations are still manifested when the animals are immunologically reconstituted with T cells or raised under germ-free conditions, thus allowing a normal life span. In this case, it seems that the absence of the thymus rather than immunodeficiency is the cause of the sexual insufficiency (576). A similar situation occurs in chickens in which the bursa of Fabricius is surgically removed during embryonic life. These animals, in addition to lacking mature B lymphocytes, show a complete atrophy of the oviduct at hatching, i.e. before they are exposed to environmental antigens. If a bursa is grafted during embryonic life, this defect is not manifested (577). Therefore, a phenotypical association seems to exist between the function of primary lymphoid organs that control the development of the immune system and the reproductive capacity. Once again, it appears that this association reflects a selective force to impede the reproduction of immunodeficient animals, while favoring the reproduction of individuals capable of developing an efficient immune system. In summary, there are indications that immune-neuroendocrine interactions may also contribute to natural selection. When the hyperproduction of endogenous immune cytokines during transmissible diseases becomes deleterious, this results in a negative selective force. In this case, the

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use of appropriate cytokine antagonists and blockers at certain stages of a disease may constitute an efficient way to abolish deleterious immune-mediated neuro-endocrine and metabolic derangements. V. Outlook A. The immune system as a diffuse, sensorial receptor organ

Information derived from stimuli from outside or inside the organism is conveyed to the brain by specialized sensory organs or receptors. Peripheral recognition and the initial processing of this information are the first steps of any sen- * sory event. Which of the signals received by the CNS will become cognitive depends on adaptative programs integrated at CNS levels. In analogy to a sensorial organ, the first step in any immune event is the recognition of the stimuli. Immune cells are specialized, not only to detect foreign antigens, but also to distinguish normal from modified self- 1 antigens. Self antigens that are present on cell membranes and body fluids could be considered as biological markers of cell and tissue constancy and integrity. This implies that immune cells, by using their large diversity of receptors, can perceive an internal image of body constituents and react to particular distortions of this image. It is now possible to add that information processed by the immune system can also ^ be transmitted to the CNS or to brain-controlled structures. Several messengers released by immunological cells, such as lymphokines and monokines, certain complement fractions, immunoglobulins, histamine, serotonin, mediators of inflammation, and thymic hormones, could serve as mediators of immune-CNS communication. Depending on the type of antigenic stimulus, different possible combinations of subsets of lymphoid and accessory cells and their soluble * products can occur. Thus, it is conceivable that there exists a code based on combinations of soluble messengers that could inform the CNS about the type of immune response in operation. Also, information about the site of an ongoing immune response could be transmitted by stimulated nerve fibers in the "strategically" located lymphoid organs or in tissues where the immune response takes place. In our view, the existence of an afferent pathway from the immune system to the CNS (281,279) implies that the immune system is a receptor-sensorial organ. * The sensory function of the immune system does not imply that the CNS will always react to signals derived from immune cells. As is the case with most information that the v brain receives, immune messages would be subject to filtering mechanisms. A neuro-endocrine response to immune signals occurs in a threshold-dependent manner, and only seldom do such responses become cognitive. A cognitive sensation is expected to be more often related to stimuli that occur as a consequence of the disease rather than to the immune response that the causal agent of the disease elicits. Apart from the direct evidence already discussed that activation of the immune system can affect brain functions, another phenomenon might reflect the reception of signals " from immune cells at CNS levels. It is well documented that the magnitude of certain immune responses can be behaviorally conditioned (223-225). In our view, one of the mech-

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anisms that underlies this phenomenon is based on the conditioning of neuro-endocrine responses related to changes in the activity of the immune system. This neuro-endocrine response that is integrated at CNS levels would ultimately mediate the conditioned stimulation or inhibition of the immune response. This would constitute a further proof of the sensorial capacity of the immune system since it implies that this system is capable of informing the brain about the effect of the unconditioned stimuli, e.g. an immunosuppressive agent, on immune cells. B. Is that all? Endocrine feedback mechanisms and changes in certain general variables such as glucose concentration in blood are classic processes that serve to signal the brain about peripheral events. From the evidence discussed in the previous sections, it is now possible to add that cells of the immune system, through the production of certain cytokines and other mediators, can also convey information to the CNS. When cytokines function as mediators of an afferent pathway to the brain, they could be considered as part of a retro-hormonal signaling system. The question that arises is whether the evidence obtained from immune cells could reflect a more general process by which other cells of the body could also inform the brain about their functional state. As well as immune cells, other types of cells receive signals from outside the body, and, in all cases, are subject to intrinsic, genetically determined mechanisms that give rise to products that control cell differentiation, turnover, and repair during different stages of life. Many of these products either do not leave the cell or cannot reach the CNS. Furthermore, most cells are exposed to multiple autocrine and paracrine signals and they establish dynamic contacts with other cells. This constellation of peripherally generated signals has to be considered to understand how hormones, neurotransmitters, and neuropeptides exert their regulatory functions and serve to integrate different body systems. As a consequence of local stimuli, changes in the functional state of a cell could occur. Thus, when a given hormone or neurotransmitter reaches this cell, its final effect would be almost unpredictable and, therefore, difficult to control at CNS levels. The brain would need accurate information about peripheral events to monitor the efficiency of neuroendocrine regulatory mechanisms and to adjust the set point for the regulation of certain variables during different stages and conditions of life. As mentioned above, certain cytokines could provide the information derived from immune cells. However, at present there is not sufficient experimental evidence of the existence of retro-hormonal pathways to the brain mediated by products released by other key peripheral cells. One example of this type of messenger could be the product of a recently cloned gene expressed specifically by adipocytes which, as suggested by the authors, may affect CNS structures that regulate the size of the body fat depot (578). Although more direct evidence is necessary, this example may indicate that peripheral cells other than immunological and classic endocrine cells can also communicate with the CNS.

89

Acknowledgments We thank Dr. G. P. McGregor for reviewing the manuscript and S. Petzoldt for editorial help.

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