Immunoregulators in the nervous system.

Neuroscience& BiobehavioralReviews,Vol. 15, pp. 185-215. ~ PergamonPress plc. 1991. Printed in the U.S.A.

0149-7634/91 $3.00 + .00

Immunoregulators in the Nervous System C A R L O S R. P L A T A - S A L A M / ~

School of Life and Health Sciences University of Delaware, Newark, DE 19716 R e c e i v e d 21 J u n e 1990

PLATA-SALAM,/~N, C. R. lmmunoregulators in the nervous system. NEUROSCI BIOBEHAV REV 15(2) 185-215, 1991.--The nervous system, through the production of neuroregulators (neurotransmitters, neuromodulators and neuropeptides) can regulate specific immune system functions, while the immune system, through the production of immunoregulators (immunomodulators and immunopeptides) can regulate specific nervous system functions. This indicates a reciprocal communication between the nervous and immune systems. The presence of immunoregulators in the brain and cerebrospinal fluid is the result of local synthesis--by intrinsic and blood-derived macrophages, activated T-lymphocytes that cross the blood-brain barrier, endothelial cells of the cerebrovasculature, microglia, astrocytes, and neuronal components--and/or uptake from the peripheral blood through the blood-brain barrier (in specific cases) and circumventricular organs. Acute and chronic pathological processes (infection, inflammation, immunological reactions, malignancy, necrosis) stimulate the synthesis and release of immunoregulators in various cell systems. These immunoregulators have pivotal roles in the coordination of the host defense mechanisms and repair, and induce a series of immunological, endocrinological, metabolical and neurological responses. This review summarizes studies concerning immunoregulators-such as interleukins, tumor necrosis factor, interferons, transforming growth factors, thymic peptides, tuftsin, platelet activating factor, neuro-immunoregulators--in the nervous system. It also describes the monitoring of immunoregulators by the central nervous system (CNS) as part of the regulatory factors that induce neurological manifestations (e.g., fever, somnolence, appetite suppression, neuroendocrine alterations) frequently accompanying acute and chronic pathological processes. Immunoregulators Immunomodulators Neuroendocrine system Interleukins Review

Immunopeptides Tumor necrosis factor

THE nervous and immune systems consist of complex networks of cells that monitor specific signals and respond in a specific manner. The nervous system, through the production of neuroregulators (neurotransmitters, neuromodulators and neuropeptides), can regulate specific immune system functions. In addition to this humoral signaling, there are morphological substrates--innervated immune organs such as the thymus, spleen, and bone marrow (290,428)--which also contribute to the communication from the nervous to the immune system (Fig. 1). The immune system produces a variety of chemical factors that exert specific immunoregulatory actions. These immunoregulators (immunomodulators and immunopeptides, substances with either stimulating or inhibiting activities on certain functions of the immune system) also possess specific neuromodulatory activities. This establish a bidirectional communication between the nervous and immune systems (Fig. 1). Research on the modulation of the immune system by neuroregulators has been receiving considerable attention (see section on neuroregulators as immunoregulators); however, modulation of nervous system functions by immunoregulators has been little studied. This review summarizes the representative studies and reviews concerning the effects of various categories of immunoregulators on the nervous system. This review also describes that immunoregulators induce various neurological manifestations occurring during acute and chronic pathological processes.

Central nervous system Interferons Tuftsin

Immune system Platelet activating factor

GENERAL DESCRIPTION

Significance of hnmunoregulators lmmunoregulators have pivotal roles in the coordination of the host defense mechanisms and repair. The cellular cooperation in the expression of immune and inflammatory responses is dependent on peptides released from lymphocytes (lymphokines), the mononuclear/phagocyte system consisting of monocyte and macrophages (monokines) and other cell types. This heterogeneous group of mediators is collectively termed cytokines (114). Cytokines have multiple biological effects on a variety of target cells. A simplified schematic representation of the cytokine-immunoregulatory network is shown in Fig. 3.

Mode of Action of hnmunoregulators lmmunoregulators with neuroactive properties, as well as neuroregulators with immunoactive properties, can act in an autocrine manner (on the same cell that produces them), and/or paracrine manner (on neighbor cells), and/or endocrine manner (on distant target sites) (Figs. 2 and 3). For example, after induction of an immune response, immune system cells synthesize and release immunoregulators which activate specific functions in the same cell that produces them (autocrine effect) (Fig. 3), or convey messages to other components of the immune system (paracrine

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ABBREVIATIONS ACTH AD BBB BCDF BCGF BSF-I BSF-2 CNS CRF CSF CSFa CVOs EGF FSH GCSF GM-CSF HLA ICV IFN IL IP IRs IV LH LHA MHC MSH mol.wt, NE NGF NLK NRs OVLT PA-AH PAF PGE PF4 RH TGF TNF TRF TRH TSH VIP VMH

adrenocorticotropic hormone Alzheimer's disease blood-brain barrier B-cell differentiating factor B-cell growth factor B-cell stimulating factor-I B-cell stimulating factor-2 central nervous system corticotropin-releasing factor cerebrospinal fluid colony-stimulating factor circumventricular organs epidermal growth factor follicle-stimulating hormone granulocyte colony-stimulating factor granulocyte-macrophage colony-stimulating factor human leukocyte antigen intracerebroventricular interferon interleukin intraperitoneal immunoregulators intravenous luteinizing hormone lateral hypothalamic area major histocompatibility complex melanocyte-stimulating hormone molecular weight norepinephrine nerve growth factor neuroleukin neuroregulators organum vasculosum lamina terminalis preoptic area-anterior hypothalamus platelet activating factor prostaglandin E platelet factor 4 recombinant human transtbrming growth factor tumor necrosis factor T-cell replacing factor thyrotropin-releasing hormone thyroid-stimulating hormone, thyrotropin vasoactive intestinal peptide ventromedial hypothalamus

effect) (Fig. 3), and to other distant target sites including brain and the neuroendocrine system (endocrine effect) (Figs. 1 and 2).

bnmunoregulators in the Nervous System The presence of immunoregulators (immunomodulators and immunopeptides) in the brain and cerebrospinal fluid (CSF) is a result of local synthesis and/or specific uptake from the peripheral circulation. Local synthesis. Various cell types have the ability to synthesize and release immunoregulators in the central nervous system (CNS). These cell types include intrinsic and blood-derived macrophages (223), activated T-lymphocytes that cross the bloodbrain barrier (BBB) (451,490), endothelial cells of the cerebrovasculature (38), microglia (of monocytic origin) ubiquitously distributed in the brain (161, 169, 223, 384), astrocytes (38, 90, 148), and neurons (50-52). Microglial cells and/or astrocytes mediate many of the functions of the macrophages including antigen presentation (see the General Discussion section); phagocytosis (90); and synthesis and release of immunoregulators

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FIG. 1. Communication between the nervous and immune systems. (1) neuroimmune pathway through neuroregulators (NRs, neurotransmitters, neuromodulators and neuropeptides). (2) Immunoneural pathway through immunoregulators (IRs, immunomodulators and immunopeptides). (3) Neuroimmune pathway through neuroanatomical substrates. (4) Microbial products, toxins, injury, and inflammation are trigger factors for synthesis and release of immunoregulators either by immune or CNS cells.

(38, 90, 148, 223, 384), prostaglandins, apolipoprotein E, complement molecule C3, and growth factors (266, 365, 372, 447). Activated T-lymphocytes can cross the BBB (451,490), patrol the CNS, recognize specific antigens on the surface of glial cells (390, 489, 490), and interact with them through the release of immunoregulators (489). Consequently. microglia, astrocytes, macrophages, and T-lymphocytes may participate in CNS immune and inflammatory responses through cell-to-cell contact and/or through release of immunoregulators that bind to specific cell surface receptors. Uptake fi'om the peripheral circulation. Transport of various immunoregulators from the peripheral circulation to the nervous system (brain-CSF) has been demonstrated (13,14). A bidirectionally regulated transport system for immunoregulators across the BBB is proposed (14). Immunoregulators released in the periphery may gain slow access to brain interstitial fluid in the circumventricular organs (CVOs) that lack BBB (e.g., area postrema, median eminence, and organum vasculosum lamina terminalis or OVLT) (44). This may be followed by selective transport to other brain sites or into ventricular CSF (355). Evidence also suggests that the choroid plexus, which constitutes the blood-CSF barrier. is a nonspecific pathway for rapid peptide transport into brain (503). Choroid plexus has high concentrations of receptors for immunoregulators (137) and choroid plexus cells are capable of taking up immunoregulators present in the CSF (336); choroid plexus is also able to present foreign antigens to peripheral helper T-lymphocytes (336). Immunoregulators and other peptides also have the ability to pass from the CSF into the peripheral blood (46,356), possibly via absorption into the superior sagittal sinus at the arachnoid villi (355). It is also speculated that the large

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FIG. 2. Mode of action of neuroregulators and immunoregulators. These chemical substances can either act in an autocrine manner (on the same cell that produces them), and/or paracrine manner (on cells near their sites of synthesis and release), and/or endocrine manner (on distant target sites). For simplicity only immunoregulators are included. Abbreviations: IRs, immunoregulators; CNS. central nervous system; BBB, blood-brain barrier; CVOs, circumventricutar organs.

number of mast cells located on BBB blood vessels--in thalamus, hippocampus, lateral and third ventricles--could release their mediators during immune activation and consequently, increase the permeability of BBB blood vessels to immunoregulators (344).

hnportance of bnmunoregulators in the Nervous Systenz Infection, injury (bums, trauma, surgery), toxins, immunological reactions, acute and chronic inflammatory processes, malignancy, and necrosis stimulate the synthesis and release of immunoregulators (32, 38, 110, 303, 321). These pathological processes induce a series of immunological, endocrinological, metabolical, and neurological responses (111). Immunoregulators released during these processes participate in the mediation of these alterations (21,111). The discussion presented in this review describes that immunoregulators released during pathological processes are part of the regulatory signals that induce neurological manifestations--e.g., fever, somnolence, anorexia, which frequently accompany acute and chronic disease--by a direct action in specific CNS target sites. Evidence of immunoregulator effects in the nervous system is rapidly expanding. Knowledge of biological actions of immunoregulators on immune system target sites may provide a basis for understanding the biological actions and potential mechanisms activated in the nervous system. On the basis of this, a brief description concerning immunological actions of each immunoregulator is included. INTERLEUKIN 1 (IL-I)

Chemical Characteristics IL-1 is present in two molecular forms, I L - l a and IL-113 (296). I L - l a consists of 159 amino acids (mol.wt. of approximately 17,500) and IL-113 of 153 amino acids (mol.wt. of approximately 17,500) (296). Both molecular forms are comprised of beta-folded sheets (112). I L - l a and IL-113 are coded by separate genes 1o-

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FIG. 3. Simplified schematic representation of the immunoregulatory network. Microbial products (e.g., lipopolysaccharide or muramyl peptides), toxins, injury, and inflammation induce the release of interleukin-1 (ILl), tumor necrosis factor (TNF), and granulocyte colony-stimulating factor (GCSF) from phagocytic cells (monocyte/macrophages). The term "interleukin" refers to the pivotal property of immunoregulators to function as chemical links between leukocytes. TNF acts in an autocrine manner to stimulate IL-I production by macrophages. IL-I activates T-cells (produced by the thymus), and activated T-cells produce IL-I, 1L-2, IL-3, IL-4, B-cell differentiating factor (BCDF), interferons (IFNs), and granulocyte-macrophage CSF (GM-CSF). The subsequent interaction of IL-2 with IL-2 receptors (autocrine effect) induces T-cell proliferation culminating in the production of functional subsets of cells with cytotoxic, suppressor, suppressor inducer, direct helper, and natural killer functions. The cytotoxic T-cells mediate cellular immunity by a direct toxic effect. reacting directly with cell membrane-associated antigens. The helper function of T-cells refers to their production of factors which preferentially promote B-cell growth factor (BCGF) and factors which preferentially promote B-cell differentiation (BCDF); suppressor T-ceils also regulate B-cell proliferation. B-cells are generated from hematopoietic stem ceils within the fetal liver and later the bone marrow. Interferon-'), (IFN-3,) activates macrophages and amplifies TNF release by macrophages. IL-I is also produced by B-cells and acts in an autocrine manner. The principal steps that lead to the production of antibodies are: specific activation of memory B-cells, proliferation of B-cells, and differentiation of B-cells into antibody-producing cells. These three stages are regulated by IL-I, IL-2, BCGF, BCDF, and IFN-3, acting on B-cells. Antigens may also activate B-cells through surface antibodies. IL-3 and GM-CSF produced by activated T-cells induce hematopoiesis by stimulating bone marrow stem cells; IL-3 also induces proliferation and differentiation of immature lymphocytes. IL-7 induces proliferation of B-cell precursors. IL-4 and IL-5 induce activation, growth and differentiation of B-cells. IL-6 induces the final maturation of B-cells into immunoglobulin-secreting cells. Modified from Plata-Salam,'in (366) with permission.

cated on chromosome 2 (80, 163,487). The two IL-1 forms share only partial amino acid homology in the same species (26% for human I L - l s versus human IL-113) (I 12). Between species, however, I L - l a presents an amino acid homology of approximately 70% between human and mouse I L - l a forms and of nearly 88% between IL-l[3 forms (112). Despite differences between I L - I a and IL-113, both bind to the same receptor (117) and induce similar biological effects on a variety of target cells (38).

Synthesis Peripheral. Both molecular forms of IL-1 are produced by stimulated monocyte/macrophages, lymphocytes, fibroblasts, en-

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dothelial, adrenal chromaffin, and other cells (109,112). The monocyte/macrophages synthesize large amounts of IL-I (112), and IL-113 mRNA predominates over that of IL-Ia in rodent and human cells (112). Central. Brain intrinsic macrophages (223), cerebrovascular endothelial cells (38), microglia (169, 171, 172, 223, 384), astrocytes (90,148), and neurons (50,52) have the ability to synthesize and release IL-1 in response to the appropriate stimuli. IL113-1ike immunoreactive cell bodies in human brain are found in hypothalamic arcuate nucleus, preoptic and periventricular regions, and retrochiasmatic area (52). In addition, IL-113-1ike immunoreactive fibers are present in human hypothalamic regions including the paraventricular, ventromedial, arcuate and supraoptic nuclei, lateral hypothalamic area (LHA), median eminence, subfornical organ, and posterior hypothalamus (50,52); IL-113like immunoreactive fibers are also markedly present in the central nucleus of the amygdala, bed nucleus of the stria terminalis, midline thalamic nuclei, periaqueductal gray matter, locus coeruleus, parabrachial nucleus, and nucleus tractus solitarius (52). IL-113 mRNA has been detected in rat hippocampus and cerebral cortex (25), strongly suggesting biosynthesis of IL-113 in the CNS. IL-l-like immunoreactivity has also been found in peripheral nerves (40). The presence of IL-I in brain-CSF is not only a result of local synthesis by brain cells, but is also due to a concentration of IL-1 from the peripheral blood. A bidirectional transport of IL-let across the BBB has been demonstrated (14). In this study, recombinant human IL-let (rhlL-let) entered multiple brain regions with over 40% entering the cerebral cortex (which lacks CVOs) by a specific transport system. The hypothalamus, however, had the highest entry rate (14). In addition, activated T-lymphocytes may cross the BBB (451,490) and release IL-I in particular brain target sites. Release of IL-1 in the Nervous System

Various agents induce the synthesis and release of IL-1 by CNS and peripheral cells. These agents include bacterial endotoxin (Escherichia coli lipopolysaccharide) (112, 116, 271,513), neurotropic viruses (271), and activators of protein kinase C (112). Intracerebroventricular (ICV) administration of endotoxin--one of the most potent inductors of IL-I production by stimulating its transcription (112)--induces the appearance of IL-1 in the CSF (84); this effect was not observed after intravenous (IV) administration of endotoxin indicating synthesis and release of IL-1 in the CNS. IL-l-like activity in the CSF has been detected in patients with degenerative diseases (175) and in chronic encephalomyelitis in guinea pig (454). IL-113 was identified in CSF of patients infected with human immunodeficiency virus type 1 (164). IL-I has also been detected in brains of Alzheimer's disease (AD) patients (227) including increases of IL-113 mRNA in the superior frontal gyrus of young AD patients (391). This evidence suggests a participation of IL-I in the astrogliosis (astrocyte proliferation and reactivity) of AD. In other study, increased IL-1 immunoreactivity was found in microglia of brains from patients with AD and Down syndrome (183); the same cells were immunoreactive to IL-l and S-100 protein and it was proposed that increased expression of S-100 protein in Down syndrome may be a result of increased IL-I (183). Thus, a variety of acute and chronic pathological processes of central or peripheral origin may result in the appearance of IL-1 in the CNS; this may indicate ongoing inflammatory, immunological, and/or neurological reactions dependent on IL-I within the CNS (119,454). 1L-1 Receptors

The IL-I receptor is an 80 KDa membrane macromolecule

PLATA-SALAMAN

which binds IL-let and IL-113 (112,117). The IL-I receptor contains an extracellular domain of 319 amino acids composed of three immunoglobulin-like domains (423); the cytoplasmic domain of the receptor contains 217 amino acids (423). The IL-1 receptor in the CNS has a similar mol.wt, to that of receptors on T-cells and fibroblasts (137). In the CNS, however, a different type of receptor which binds IL-113 more potently than IL-let has also been identified (229). IL-1 receptors are densely localized in the olfactory bulb, hippocampus, cerebellum, cerebral cortex, choroid plexus, and hypothalamus (137). Specific IL-113 receptors are also localized in the same regions, e.g., cerebral cortex and hypothalamus (229). The nature of the interaction between IL-I and its receptor in the CNS remains unclear. Biological Actions of IL-1 Actions in the immune system. IL-1 participates in the activation and differentiation of lymphocytes (Fig. 3). stimulation of immunoregulator production (see the General Discussion section), and in the induction of chemotaxis on monocytes, neutrophils, and lymphocytes (110,114). Membrane-bound IL-I participates in antigen presentation and in the induction of autocrine and paracrine effects (112). For review concerning immunological effects of IL-I see (110). Actions in the nervous system. Effects on growth and differentiation. IL-1 has been implicated as a regulator of glial cell growth and proliferation (170,172). These effects have been observed in astrocytes (172) and astrocytoma cells (25 I). A direct participation of IL- 1 in brain gliosis has also been proposed (170). Evidence suggests that IL-I may play a role in the determination of neuronal survival during development (53), and in the regulation of CNS growth during embryogenesis (172). Neuromodulatol 3, effects. Various neuromodulatory effects of IL-1 have been reported including: 1) a stimulation of central noradrenergic systems (225); rhlL-113 stimulates the release and metabolism of norepinephrine (NE) from the hypothalamus (225,352). This effect is specific since no comparable changes in the content of other neurotransmitters were detected (225). IL-let also increases levels of epinephrine and vasoactive intestinal peptide (VIP) in cultured adrenal chromaffin cells (128); 2) an enhancement of CNS opioid receptor binding (497); 3) a potent hyperalgesia reported when rhlL- Iet (331 ) or rhlL- 113(143) is administered peripherally or centrally. This effect is not affected by the opiate antagonist naloxone (143,331); 4) a regulation of nerve growth factor (NGF) synthesis (272,346) by increasing NGF mRNA (157); 5) a regulation of beta-amyloid precursor mRNA levels which is involved in amyloid formation in AD (25); 6) a stimulation of eicosanoid production by astrocytes, in particular prostaglandin E (PGE), thromboxane B 2, and other arachidonic acid metabolites (194,230). Protein kinase C is involved in this biological action of IL-I (194). The ability of IL-I to induce PGE synthesis is expressed through many local and systemic effects; 7) an increase of pro-opiomelanocortin mRNA expression in pituitary cells (56); 8) an induction of cognitive changes by decreasing glucose metabolism (227); 9) a decrease of EEG synchronization after ICV administration of IL-I (398); and 10) a delay in conduction within myelinated afferent pathways (55). Effects on the neuroendocrine system. Peripheral administration of IL-I induces synthesis and release of somatostatin (399) and corticotropin-releasing factor (CRF) (26, 399, 469) from rat hypothalamus. The stimulatory action of IL-113 on CRF release from rat hypothalamus in vitro appears to be modulated by glucocorticoids (64). IL-lot and IL-113 also induce the synthesis and release of various pituitary hormones including adrenocorticotropic hormone (ACTH) (19, 29, 31, 61, 471), thyrotropin (19, 29, 61), growth hormone (19, 29, 61, 471), luteinizing hormone (LH) (19, 29,505), follicle-stimulating hormone (FSH) (505) and pro-


lactin (505) secretions. Other studies, however, have shown inhibition of LH (385) and prolactin (29) secretions. ICV administration of rhlL-lc~ has been reported to inhibit LH release (385), whereas rhlL-113 blocks the progesterone-induced LH surge (226) with more potency than rhlL-la (226); rhlL-l(x and rhlL-113 also significantly suppressed LH-releasing hormone release from the medial basal hypothalamus-preoptic area in vitro (226). The significance of these discrepancies conceming LH release in vitro and in vivo remains to be determined. It is proposed that prostaglandins are mediators of IL-l[3-induced CRH/ACTH release (230). Moreover, IL-113 modulates prolactin secretion through changes in adenylate cyclase and calcium fluxes (145,402). IL-I, via protein kinases (132), also enhances the release of beta-endorphin induced by CRF, VIP, forskolin, NE, phorbol ester, and isoproterenol. It should be noted that systemic IL-I may influence pituitary hormone release by passage across the median eminence (a CVO). Studies in culture show that the effects on pituitary hormone release occur at concentrations within the range of IL-I in serum (29). IL-1 also acts directly on the adrenal gland to increase glucocorticoid synthesis (392). An integrative view of a feedback loop involving IL-I and the neuroendocrine system is described in the General Discussion section. Pyrogenic effect. IL-I induces fever through a prostaglandin-dependent mechanism activated in hypothalamic structures (98, 99, 195, 317) (see the General Discussion section). Fever induced by ICV administration of IL-I is also dependent on the central catecholaminergic system, since pretreatment with 6-hydroxydopamine (a catecholamine-depleting agent) blocks the IL-l-induced fever in rodents (348). Somnogenic effect. IL-I induces slow-wave sleep in rats (463), rabbits (247, 417,484) and cats (452) (see the General Discussion section). The somnogenic effect of IL-1 could be associated to the increased sleep observed during infection and chronic diseases. Other effects induced by IL-I such as decreases of locomotor activity (347,368) and exploratory behavior (436) may also be related to the sleep-inducing effect of 1L-1. IL-I and feeding regulation. a. Peripheral administration. Initial studies reported that microgram doses (as high as 500 txg/kg/day) (146) of IL-1 suppressed food intake after intraperitoneal (IP) administration into fasted rats (286), and freely fed rats (146) and mice (313). In mice, IL-la suppresses food intake at ten times lower concentrations than those required to induce fever (313). This evidence suggests a direct effect of IL- 1 suppressing food intake and excludes an indirect effect secondary to fever. In other reports, chronic infusion of 2 Izg/day (322) or 3-6 i.tg/day (347) recombinant murine IL-lc~ from osmotic minipumps also suppressed food intake in rats. Chronic infusion, however, was accompanied by tolerance to the food intake suppressive effect after a few days (322,347). It is proposed that IL-I lowers the set point for body weight since prior body weight reduction diminished the feedingsuppressive effect of IL-I and food-deprived rats were hyperphagic initially regardless of the IL-I administration (322). In another study, ->4 i.Lg/kg rhlL-l[3 and recombinant murine I L - l a (and to a lesser extent rhlL-la) suppressed food intake in rats on chow diets (200). The food intake suppressive effect by IL-1 was abolished in rats fed with fish oil diet (200). In rodents and humans, fish oil has been shown to decrease IL-l-stimulated prostaglandin-E2 production in various tissues (125,200). Chronic infusion of IL-I also suppressed food intake in rats fed with chow and corn oil, but had no effect in rats fed with fish oil (200). The implications of these findings are described in the General Discussion section. It is also interesting to note that normal aging in rats decreases the sensitivity to the food intake suppressive effect of rhlL-113 (200).

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Administration of factors that induce release of IL-I also results in food intake suppression. IP administration of muramyl dipeptide (the minimal immunological active structure of gram positive bacterial cell walls) or endotoxin suppresses food intake in rats by decreasing meal frequency without affecting meal size (255). IV administration of low doses of endotoxin decreased food intake but increased water intake in rats (129); this may indicate behavioral specificity. b. Central adminiso'ation. IL-1 acts directly in the CNS to suppress food intake. ICV administration of low doses (1-13 ng/ rat) of rhlL-113 suppresses food intake (368). This effect is dose dependent, specific to the nighttime and reversible (368). Food intake suppression by IL-1 is mediated by the CNS, since peripheral administration of rhlL-113 in doses equivalent to or higher than those administered centrally has no effect on food intake (368). The IP doses of rhlL-l[3 administered in this study (13 and 200 ng/rat) were still much lower than the doses reported to suppress food intake when administered peripherally which are in the microgram range (146, 200, 286, 313,322, 347,472,473). c. Action mechanism of IL-1 suppressing food intake. Electrophysiological studies in the LHA, considered an important site for the regulation of feeding, have shown that electrophoretically applied rhlL-113 specifically suppresses the neuronal activity of 86% glucose-sensitive neurons (368), but has little effect on glucose-insensitive neurons. Since glucose-sensitive neurons participate in hunger (368), this evidence supports a direct and specific effect of IL-II3 in the CNS to suppress feeding. The participation of hypothalamic feeding-associated sites in the suppression of food intake by IL-113 may interact with other factors. IL-1 decreases gastric emptying and motility (479); increases circulating levels of glucagon after peripheral (109) administration; and increases insulin levels after peripheral (109,254), ICV (88,89), or intrahypothalamic (89) administration through prostaglandin-dependent mechanisms (88). All these factors have been shown to suppress food intake (318, 367, 369, 502). As proposed by Uehara et al. (473), food intake suppression by IL-1 may also be dependent on CRF, since IL-I stimulates the release of CRF (26, 399, 469); CRF acts centrally to suppress food intake (318); and food intake suppression by IL-1 (1-25 I~g/rat, 1P) is diminished by the immunoneutralization of CRF in the CNS (473). IL-1 also induces sleep (47, 247, 417, 452, 463, 484) and decreases locomotor activity (347,368). These effects may also participate in the food intake suppression by IL-1. It is also proposed that a conditioned taste aversion may contribute to the food intake suppression during gram positive (by muramyl dipeptide) or gram negative (by endotoxin) bacterial infection (255), or after IP administration of IL-1 (1-10 Ixg) (459). Prostaglandins appear to participate in the food intake suppression by IL- 1 since preinjection of ibuprofen or indomethacin, inhibitors of prostaglandin synthesis, blocked the food intake suppression by IL-I (200,472). It is proposed that indomethacin might be clinically useful for improvement of the food intake suppression observed in patients with acute infectious diseases (472). It is interesting to note that IL-I shows a sequence homology of approximately 27% with acidic and basic fibroblast growth factors [see (365)]; these growth factors also suppress food intake by direct and specific action in the LHA (364,365). Similar effects of IL-1 and fibroblast growth factors on mitogenesis (365), food intake (365), and other parameters (365) may indicate that these peptides possess a similar mechanism(s) of action or function dependent on a specific homologous region present in all three peptides.

Release of IL- 1 in Other Conditions Circulating levels of IL-1 are increased following vigorous

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physical exercise (67), after ovulation (66), and after exposure to ultraviolet light (112). It is proposed that IL-1 may participate in the sleepiness and food intake suppression following exercise (67). This indicates a participation of IL-I in physiological phenomena. Evidence also supports a persistent increased IL-I secretion underlying the postmenopausal osteoporosis (350), and steroid treatment blocks this postmenopausal increase of IL-I release (350).

Other Effects of lL-I Many of the biological effects of IL-1 are clearly inflammatory. In addition to the immunological and neurological effects above mentioned, IL-I induces a series of metabolical and endocrinological alterations. These include: induction of acute-phase proteins from hepatocytes, alterations in plasma levels of nutrients and hormones, catabolic effects, and stimulation of prostaglandin production [for review see (110)]. These effects will directly or indirectly affect immunological and neurological functions. INTERLEUKIN-2(IL-2) Chemical Characteristics IL-2 or T-cell growth factor consists of 133 amino acids (mol.wt. of approximately 15,000) (180,458).

Synthesis Peripheral. IL-2 is produced by T-lymphocytes (307). Central. In the CNS, IL-2-1ike immunoreactive material has been found in rat brain regions (7,256) and in human brain (281). Although types of brain cells responsible for IL-2 production are yet to be identified microglia and intrinsic macrophages are plausible candidates (281). Release of IL-2 in the Nervous System IL-2 has been detected in the CSF of patients with multiple sclerosis (165) and various CNS lesions (249). This suggests release of IL-2 within the CNS. The decreased IL-2 production observed in schizophrenic patients remains to be confirmed (166).

PLATA-SALAM/~N

Neuromodulatot3, effects. Various neuromodulatory effects of IL-2 have been reported including: 1) an inhibition of acetylcholine release in specific CNS regions (7); 2) an increase of neuronal activity in the supraoptic and paraventricular hypothalamic nuclei after ICV administration in rats (39). Since these nuclei secrete the antidiuretic hormone, their excitation has been proposed as a partial explanation for the considerable water retention observed during IL-2 therapy (39); 3) a dose-dependent inhibition of longterm potentiation in the rat hippocampus (457). This may explain, at least in part, the memory impairment observed during IL-2 therapy; and 4) an induction of sedation and/or sleep and electrocortical activity synchronization after ICV administration of IL-2 in rats (106); much smaller doses were required to induce similar effects after administration into the locus coeruleus (106). These effects were not observed in animals pretreated with naloxone or after administration of small doses of IL-2 into the caudate nucleus, hippocampus, substantia nigra and ventromedial hypothalamus (106). Effects on the neuroendocrine system. IL-2 stimulates release of [3-endorphin and ACTH in the murine pituitary cell line AtT20 (431). Evidence obtained in subjects receiving immunotherapy with IL-2, or IL-2 plus immunoregulator-activated killer cells also shows that IL-2 increases blood levels of [3-endorphin (103), ACTH (103,278), and cortisol (8,103). Neurotoxic effects. Several studies concerning IL-2 and the nervous system have used preparations of rhlL-2 containing acetic acid buffer or glutathione as stabilizers (363), A rhlL-2 vehicle toxicity has been described in studies of cerebrovascular permeability (124) including a disruption of the BBB (486). Studies on food intake also show a direct toxic effect of the preparations, since ICV administration of intact or inactivated rhlL-2 suppresses food intake (363). Because of its immunological activities, rhlL-2 has been used as an adoptive immunotherapy for advanced malignancies (45,131). For example, tumor-infiltrating lymphocytes expanded in IL-2 have been used for intracranial treatment of malignant glioma (239,306). IL-2 adoptive immunotherapy in human, however, is accompanied by a variety of adverse effects (104, 142,306, 309) that include fever, malaise, headache, confusion, lethargy and somnolence, nausea, and increases in the cerebral water content of both gray and white matter (400).

IL-2 Receptors The IL-2 receptor structure presents an external binding domain of 220 amino acids, a transmembrane domain, and a cytoplasmic domain of 13 amino acids (430). This membrane complex presents three different affinity forms and is composed of at least two subunits (179). Specific IL-2 receptors are present in the rat brain (7,256), in particular, in the hippocampus (7), olfactory bulb, cerebellum, and corpus callosum (256). Evidence also suggests that sympathetic neurons may have a specific receptor for IL-2 (196).

Biological Actions of IL-2 Actions in the immune system. IL-2 acts in an autocrine manner to initiate proliferation of activated T-cells (114,307) (Fig. 3). IL-2 stimulates the effector function of natural killer and other cytotoxic effector cells, and participates in B-cell growth and differentiation (307,458). Actions in the nervous system. Effects on growth and differentiation. IL-2 modulates oligodendroblast proliferation (24,397), and enhances sympathetic neurite outgrowth (196). This suggests its participation as a neurotrophic factor.

INTERLEUKIN-6(IL-6)

Chemical Characteristics IL-6 (also called B-cell stimulating factor-2, or B-cell differentiating factor, or interferon-beta 2) is a polypeptide of 184 amino acids (mol.wt. of approximately 26 KDa) (208, 338, 477). IL-6 is synthesized as a precursor of 212 amino acids (206). The derived amino acid sequence of rat IL-6 is 93% homologous with the mouse polypeptide and 58% homologous with the human polypeptide (456). In human, however, multiple forms of IL-6 (phosphoglycoproteins of 23-30 KDa) are secreted by different tissues (304).

Synthesis Peripheral. IL-6 is synthesized by various cell types including fibroblasts, endothelial cells, monocytes, macrophages, T- and B-cells (376, 456, 476), hepatocytes, and endometrial cells (376,456). IL-6 is also synthesized by transformed cell lines including the hepatoma (376), epidermoid carcinoma (376,456), cardiac myxoma (207), and uterine carcinoma cells (207). Central. IL-6 is synthesized in brain and anterior pituitary cells (376, 478, 508). IL-6 is synthesized and released by normal or


virus-infected microglial cells and astrocytes (153,384). IL-6 mRNA has been detected in IL-l-stimulated glioblastoma and astrocytoma cell lines (508). High concentrations of IL-6 have been found in human hypothalamus and other brain structures (376). Release of IL-6 in the Nervous System IL-6 synthesis and release can be induced by bacteria and bacterial products (endotoxin), DNA and RNA virus agents (Sendai, influenza), trauma (burns, surgery), second messenger agonists and PGE t, immunoregulators (IL-1, IL-2, tumor necrosis factor, lymphotoxin, interferons) (see the General Discussion section), and growth factors (platelet-derived growth factor, colony-stimulating factors) (271, 376, 439, 456). In the presence of endotoxin, IL-6 is released from rat brain structures (439); the release of IL-6 from hypothalamus is much greater than the release from other brain structures like the cerebral cortex (439). Neurotropic paramyxovirus (Newcastle disease virus) also activates IL-6 gene transcription (271). IL-6 has been detected in human CSF and other biological fluids including serum, urine, and synovial and amniotic fluids (213, 338, 376, 456). Increased CSF levels of IL-6 have been found during acute CNS infections; these include bacterial meningitis (376,456), viral encephalitis (152), human immunodeficiency virus type I infection (164), and other CNS infections (213). In patients with both meningitis and bacteremia, IL-6 concentration in the CSF is 10- to 100-fold higher than in serum (199); this suggests CNS synthesis of IL-6. Increased CSF levels of IL-6 are found in 88% of patients with brain tumors (264). Increased CNS IL-6 production also occurs in experimental autoimmune encephalomyelitis (167). Thus, IL-6 is involved in a large variety of human pathological processes specially as a mediator of the host response to acute inflammation. This modulation is exerted through direct effects, and/or mediation of effects of other immunoregulators, and/or synergistic effects with other immunoregulators (see the General Discussion section). Dysregulation of IL-6 production may participate in various diseases (301). In any process, the transport of IL-6 from blood to brain through BBB and/or CVOs may be operative. For example, hyperplastic lymph nodes in Castleman's disease produce large quantities of IL-6 (301); the fever accompanying this disease may be the result of the interaction between IL-6 and hypothalamic thermoregulatory structures. Additional evidence for IL-6 transport from blood to brain has been obtained from patients with severe burns which display an inflammatory reaction (including high fever) in the absence of infection (338). IL-6 Receptors The IL-6 receptor is composed of about 468 amino acids in a glycosylated mature form of approximately 80 KDa (206,507). The IL-6 receptor contains a cytoplasmic domain of 82 amino acids, a transmembrane domain of 28 amino acids, an extracellular domain of 250 amino acids, a domain of 90 amino acids belonging to the immunoglobulin superfamily, and a signal peptide of 19 amino acids (206,507). IL-6 receptors are present in normal cells (resting T-cells and activated B-cells) and transformed cells including pheochromocytoma cell lines (206). Specific IL-6 receptors are present in the nervous system. However, receptor regulation and signaling mechanisms are unknown. Biological Actions of IL-6 Actions in the immune system. IL-6 induces the final maturation of B-cells into immunoglobulin-secreting cells (114, 176, 476) (Fig. 31. IL-6 also induces growth and differentiation of

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T-cells (507) and hematopoietic stem cells (507), and triggers acute-phase protein synthesis in hepatocytes (507). Actions in the nervous system. Effects on growth and differentiation. IL-6 is mitogenic for astrocytes (408). IL-6 acts as a neurotrophic agent inducing growth and differentiation of nerve cells (507). Evidence also shows that IL-6 is able to differentiate PCI2 cells into neuronal cells (401) and supports neuronal survival of cholinergic neurons in vitro (190). Neuromodulatol 3, effects. IL-6 has the ability to induce secretion of NGF by astrocytes (153). This effect may participate in CNS development mechanisms. It is interesting to note that IL-6 produced in the CNS might be involved in the CNS production of immunoglobulins (147). Effects on the neuroendocrine system. Picomolar concentrations of IL-6 have been found to stimulate the secretion of ACTH (329,500), growth hormone (438,505), LH (438,505) and prolactin (438,505) from rat anterior pituitary cells. The IL-6-induced ACTH secretion is blocked by anti-CRF antibodies (329). IL-6 also potentiates gonadotropin-hornaone releasing factor and TRHinduced hormone release (438). 1L-6 and feeding regulation. Evidence shows that IL-6 acts directly in the CNS to suppress FI (363). ICV administration of IL-6 (15-60 ng/animal) suppresses the nighttime food intake in rats, whereas daytime food intake increases (363). This dose-dependent effect is mediated by the CNS since peripheral (IP) administration of IL-6 in doses higher than those administered centrally has no effect on food intake (363). TUMOR NECROSIS FACTOR (TNF)

Nomenclature and Chemical Characteristics A factor induced by endotoxin is called TNF-a (32, 38, 294). This factor is characterized by its cytotoxic and/or cytostatic activity on transformed cells (32,294), but it also participates in the inflammatory response (33). TNF is related to various toxic manifestations of infections, neoplastic, or autoimmune diseases (32). Two distinct molecules--TNF (a macrophage product) and lymphotoxin (a lymphocyte product)--have similar tumoricidal activities (303,353). The designation of TNF-a/cachectin or TNF-a is used for macrophage-related TNF (38, 303, 353). TNF-a has been isolated during studies of cachexia (a progressive wasting of adipose and muscle tissues accompanied by anorexia, asthenia, and anemia) in chronic bacterial or parasitic diseases and in cancer (12, 32, 38, 294). Human TNF-a is composed of 157 amino acids (mol.wt. of 17,350) (34, 38, 222), whereas murine TNF-a presents 156 amino acids (34); in both cases, a trimeric form is the active molecule. The designation of TNF-[3 (171 amino acids for human, mol.wt, of 18,600, and 169 amino acids for murine) is used for lymphocyte-related lymphotoxin (303,353,358). Human and murine TNF-a and TNF-13 share 35% and 28% of amino acid homology, respectively (141, 268, 358). Despite the restricted sequence homology, both TNF-a and TNF-13 induce similar biological effects (34). Synthesis Peripheral. TNF-a is abundantly produced by activated macrophages (34). Lymphocytes and certain transformed cell lines are also capable of synthesizing TNF-a (34). In response to lipopolysaccharide, TNF-a mRNA levels rise within the cell by a factor of 50 to 100, while TNF-a secretion increases by a factor of about 10,000 (34). TNF-[3 is produced by T-lymphocytes, leukocytes, and transformed cell lines (358). Central. Microglial cells and astrocytes synthesize TNF-a and TNF-13 (271, 384, 386). Endotoxin induces astrocytes to synthe-

192

size and release TNF-a (271), whereas neurotropic paramyxovirus induces production of both TNF-a and TNF-[3 (271). TNF-[3 synthesis and release is also induced by other viruses, T-cell mitogens, protein kinase C activators, and other immunoregulators (358). It is also proposed that a TNF-ot-like immunoreactive neuronal system containing cell bodies and fibers is present in the hypothalamus, brainstem, and other CNS regions (51). Release of TNF in the Nervous System In humans, bacterial meningitis, but not viral encephalitis, induces an increase of TNF-ot concentration in the CSF (262). TNF-c~ has been implicated in the pathogenesis of cerebral complications of malaria (81,177), and it is proposed that both TNF-et and TNF-13 participate in chronic inflammatory CNS disorders such as multiple sclerosis (34). Various studies show that TNF-c~ increases in serum of patients with several malignancies (34), meningoccocal (482) and other septicemias (481), acquired immunodeficiency syndrome (252), and parasitic infections (406). On the basis of this evidence, it is proposed that TNF-c~ may be transported from blood to brain to interact with specific receptors in the CNS, and induce neurological manifestations accompanying chronic diseases and cachexia in cancer. TNF-c~ can also be transported from CSF to blood when administered ICV (46). This suggests a bidirectional transport system for TNF-o~ between the brain and the periphery. TNF Receptors TNF receptors are widely distributed in mammalian plasma cell membranes (403,510). TNF-ot receptor is an integral membrane complex macromolecule (mol.wt. of approximately 300 KDa) (91,403,432,510) containing 461 amino acids (426). The binding subunit of the receptor is a glycoprotein with a mol.wt. of approximately 75 KDa (218,222, 250), but details concerning the regulation of the receptor and signaling mechanisms are poorly understood. TNF-I3 binds to the same receptor as TNF-a and evokes similar biological activities to those induced by TNF-a (33). Biological Actions of TNF Actions in the immune system. TNF-c~ and TNF-13 are essential mediators of the inflammatory response (33,358). TNF-et has antitumor (34) and antiviral (308,501) activities. TNF-c~ increases the neutrophil adhesion and activation (34); increases toxicity of eosinophils (34); exerts a chemotactic effect on monocytes (34): directs maturation of thymocytes (34); and induces the release of other immunoregulators (see the General Discussion section). TNF-a-treated cells also show enhanced proliferative response to IL-2 (34). TNF-,3 has antitumor (178), antiviral (308,501), and cytotoxic (358) activities; it also induces antigen expression (358,373), activates polymorphonuclear leukocytes (358,412), and induces other effects on growth and differentiation (358). Actions in the nervous system. Effects on growth and differentiation. TNF-a and TNF-13 are mitogenic for astrocytes (215,408). This effect supports a role of TNFs in CNS development, wound healing, and reactive gliosis. Neuromodulatol S effects. Evidence shows that hypothalamic PGEz synthesis is stimulated by rhTNF-a (38). This prostaglandin modulation will induce CNS effects such as fever (see below), rhTNF-a also induces analgesia in mice by a CNS action (331): this effect is not affected by naloxone (331). In addition, rhTNF-a induces a delay in conduction within myelinated afferent pathways (55). Effects on the neuroelutocrine system. TNF-a stimulates CRF

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secretion from the hypothalamus and prolactin secretion from the pituitary gland (17). IV administration of TNF-a also decreases hypothalamic TRH and serum TSH, T 3 and T 4 in rats (354). This suggests an involvement of TNF-a in the regulation of the neuroendocrine system. Pyrogenic effect. TNF-a is capable of inducing fever (36,113) through direct effects on hypothalamic neurons, and through indirect effects due to the induction of IL-I release (110) (see the General Discussion section). Evidence also suggests that endogenous TNF-a participates in eliciting fever in response to endotoxin (232,328); IV administration of monoclonal antibodies to TNF-a suppressed the biphasic fever evoked by endotoxin administration (232,328). Thermogenic effect. TNF-c~ has been shown to stimulate thermogenesis by a direct action in the CNS (34,87). This effect might participate in the waste of tissue and body weight loss observed during cachexia. Somnogenic effect. Peripheral or central administration of rhTNF-ct induces stow-wave sleep in rabbits (47,417) (see the General Discussion section). TNF and Feeding Regulation. a. Peripheral administration. Evidence shows that IV administration of rhTNF-o~ in mice (291,292), and IP administration of rhTNF-cc in mice (313,433) and rats (149,467) suppress food intake and body weight. These effects have been obtained with acute or chronic administrations of micromolar doses (e.g., 250 txg/kg, IP) of rhTNF-c~. b. Central administration. ICV administration of low doses (50-500 ng/rat) of rhTNF-a suppresses food intake (368). This effect is specific as indicated by food intake suppression only during the nighttime (368). Food intake suppression by TNF-a is also mediated through direct action in the CNS, since IP administration of rhTNF-c~ in doses equivalent to those administered centrally has no effect on food intake (368). Because of its effects on feeding and potential transport from the periphery to brain, TNF-a is proposed to participate in the development of cancerassociated cachexia (313). Cancer growth is associated with food intake suppression or anorexia; after surgical removal of the tumor, or complete response to radiotherapy and/or chemotherapy, the feeding suppression disappears (461). Decreased concentrations of immunoreactive TNF plasma levels in obese subjects (79) and facilitated TNF induction during starvation (475) also provide indirect evidence of TNF participation in feeding. c. Action mechanism of TNF suppressing food h~take. Electrophysiological studies in the LHA show that, similar to rhlL113, electrophoretically applied rhTNF-a specifically suppresses 83% of the glucose-sensitive neurons tested (368). This evidence suggests a direct and specific effect in the CNS to suppress feeding. TNF-a also decreases gastric emptying (357), and enhances slow-wave sleep (47,417). TNF-~ and TNF-[3 act directly in the CNS to modulate the sympathetic outflow to brown adipose tissue (210). All these effects may participate in the food intake suppression induced by TNF. Evidence shows that the feeding suppression by TNF-a may not be mediated by prostaglandin-dependent mechanisms (292), but additional studies are required. Neurotoxic effects. Evidence shows that TNF-a might have toxic effects on glial ceils. TNF-a induces a delayed-onset oligodendrocyte necrosis and demyelination in vitro (409,435). It is suggested that these pathological changes may be due to process retraction and dysfunction of ion channels (409,435). hlteraction Between TNF and IL-I TNF-a and IL-I share many biological activities including


stimulation of growth of fibroblasts, regulation of granulocyte function, induction of fever, and food intake suppression (35, 73, 110, 2 9 5 , 3 0 3 , 3 2 1 , 3 6 8 , 3 9 6 ) . However, the potency of TNF-a and IL-I is different because of a distinct receptor system and no amino acid sequence similarity (32, 73, 294, 296). rhTNF-c~ induces the release of IL-I (33, 38, 110, 269, 270, 337) (see the General Discussion section). This indicates that some of the effects induced by TNF-a may be indirect through the induction of IL-I release. For example, the most effective dose of rhTNF-a suppressing food intake when administered ICV is 100 ng/rat (368), and in vitro studies show that rhTNF-a induces the release of IL-I with maximal effect at 50-100 ng/ml of rhTNF-a (113). B-CELL GROWTHFACTOR(BCGF) Chemical Characteristics. Synthesis and Receptors BCGF is a polypeptide of 124 amino acids (mol.wt. of 12,000) in its mature secreted form (413). BCGF is synthesized and released by activated T-cells (413). BCGF might also be synthetized in the CNS. However, several molecular forms of BCGF are known and production of one or more of these forms by CNS cells remains to be determined. Little is known about BCGF receptor structure, regulation and signaling. Biological Actions of BCGF Actions in the immune system. BCGF stimulates B-cell proliferation (176,413) (Fig. 3). Actions in the nervous system. Effects on growth and differentiation. Various molecular forms of BCGF induce astrocyte proliferation (23). This may indicate a participation of BCGF in CNS development and reactive gliosis. BCGF and feeding regulation. Human BCGF (10-30%/rat) acts directly in the CNS to suppress food intake, but with less potency than other immunoregulators (363). ICV administration of hBCGF suppresses the nighttime food intake, whereas daytime food intake increases (363). A direct effect in the CNS is proposed due to the fact that peripheral administration of hBCGF has no effect on food intake (363). INTERFERONS(1FNs) Nomenclature and Chemical Characteristics IFNs, initially characterized for their ability to "interfere" with viral replication, are functionally related proteins and glycoproteins which are classified into three different types on the basis of their physicochemical and biological properties: leukocyte or interferon-alpha (IFN-a), which is a polypeptide of 165 to 166 amino acids (mol.wt. of approximately 19,000) (361), fibroblast or interferon-beta (IFN-[3) (mol.wt. of approximately 20,000) (361), and immune or interferon-gamma (IFN-"/), which contains 133 to 136 amino acids (mol.wt. of approximately 15,200) (361) and is produced by T-lymphocytes (86, 238, 361). In man there are several subtypes of IFN-a (hIFN-al, hIFN-c~2, hlFN-~3) (37) indicating the presence of multiple, slightly different genes. Synthesis Peripheral. IFNs are produced by leukocytes, T-lymphocytes, fibroblasts, and macrophages (86,238). Central. Glial cells have been shown to produce IFNs (127,468). In rat brain, IFN-'y-like immunoreactivity has been shown in subpopulations of neuronal cell bodies and nerve terminals both in central and peripheral nervous system (273). IFNs can be pro-

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duced in brain during viral infections. For example, rabies virus and neurotropic paramyxovirus (Newcastle disease virus) induce production of IFN-a and IFN-[3 in rodent astrocytes (274). Release of IFNs in the Nervous System IFN-a has been detected in the CSF of patients with CNS infections (1). IFN-~, has been found in the CSF of mice with experimental viral encephalitis (152) and in the CSF of patients with herpes encephalitis (259). IFN-a has been detected in the sera of patients infected with various viruses including rubella, cytomegalovirus pneumonia, and acquired immunodeficiency syndrome due to HIV-I (310); IFN-[3 is also detected, in high levels, in sera of patients infected with HIV-I virus (310). Thus, various pathological processes induce the peripheral and/or CNS production of IFNs. IFN Receptors Cell surface specific receptors for IFNs are ubiquitously distributed in various cell types (361). IFN receptors are glycoproteins of approximately 130 KDa (361). IFN receptors have also been identified in the CNS (4), but the structure and regulation of these receptors and signaling mechanisms are unknown. Biological Actions of IFNs Actions in the immune system. IFNs have antiviral and antineoplastic properties, and antibacterial and antiprotozoal activities (16, 37, 142, 238). IFNs also exhibit immunomodulating activities including: maturation of resting B-cells to activate immunoglobulin synthesis (419) (Fig. 3): enhancement of natural killer cell cytotoxicity (238,480); and activation of macrophages for increased phagocytosis (238,480). Actions in the neta,ous system. Effects on growth and differentiation. IFN-a markedly inhibits astrocyte proliferation (215), while IFN--y promotes maturation of mouse CNS neurons in culture (375). IFN--,/has the ability to induce maturation of astrocytes at early developmental stages (127), but also inhibits DNA synthesis in enteric glial cells and in longterm cultured Schwann cells (122). The significance of these paradoxic effects of IFN-a and IFN-'y is unknown. IFN-a, IFN-[3 and IFN-"/ can prevent sympathetic neuronal death induced by NGF deprivation (76). This action may suggest a prevention of neuronal cell death during injury. Regulation of antigen e.~pression in the nervous O,stem (see the General Discussion section). IFNs function in regulating human astrocyte HLA-DR expression within the CNS. IFN-'y increases HLA-DR antigen expression in astrocytes (15). IFN-a and IFN-[3, on the other hand, inhibit the induction of HLA-DR expression by IFN-'y (15). Thus, IFN-'y can modify the immune status in the CNS by inducing major histocompatibility antigens. Neuromodulato~ effects. Various neuromodulatory effects of IFNs have been reported including: I) an increase in the immunohistochemical expression of the 210 KDa neurofilament subunit (370); 2) a dose-dependent stimulation of neuronal choline acetyltransferase (127) and glial fibrillary acidic protein (127) expression by IFN-',/. The cholinergic effect of IFN-',/(in cultures from embryonic human spinal cord) requires of nonneuronal cells (127). It is proposed that these cells (probably astrocytes) may activate cholinergic activity either by direct cell-to-cell contact or by indirect effects dependent on the release of soluble factors (127); 3) a modulation of central opioid functions (92) which may participate in the analgesia observed after peripheral (331) or central (43,331) administration of IFN-a; in the suppression of mor-

194

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phine withdrawal reactions (94), and in the sedation, sleep and electrocortical activity synchronization induced by IFN-o~ (106): 4) electrophysiological effects. In initial studies, IFN-a increased the activity of newborn rat and cat cerebellar (Purkinje) and cerebral cortex neurons (63). The effects observed (shortened latency, lowered threshold, tendency to repetitivityl on explants of cerebellar or cerebral cortex were long-lasting and reversible (63). In more recent studies, nficroelectrophoretic application of IFN-a altered the firing rate of single cells in several rat brain regions (93). Application of IFN-a, but not IFN-3', increased the activity of the majority of hippocampal and cortical neurons (381 ); rhlFN-a also increased the activity in 60% of cold-sensitive neurons, but decreased the activity in 65% of warm-sensitive neurons in the preoptic area-anterior hypothalamus (PA-AH) in rat brain tissue slices (332). In this study, the effects of IFN-a on thermosensitive neurons persisted in Ca"+-free/high Mg 2+ solution suggesting a direct effect on the postsynaptic membrane. It has also been shown that physiological doses of IFN-c~ suppress the activity of 61% PA-AH neurons (334), while increasing the activity of 36% of VMH neurons (334). This evidence indicates that IFN-a exerts modulatory effects on neuronal activity. It is also important to note that the effects of IFN-ot on neuronal activity following the microelectrophoretic application are blocked by naloxone (332,334). This suggests a participation of opiate-related mechanisms. In vivo experiments have also shown that ICV administration of IFN-a suppresses the PA-AH electrical activity (398): 5) an increase in EEG synchronization following ICV administration of IFN-a (398). ICV administration of IFN-a, but not IFN-[3, also increased electrocortical activity synchronization and induced sedation and/or sleep in rats (106): small doses were required to induce similar effects after administration into the locus coeruleus (106), but not into the caudate nucleus, hippocampus, substantia nigra and VMH (106); and 6) a delay in conduction within myelinated afferent pathways after intraocular injection of rhlFN-~, (551. Effects on the neuroendocrine system. Stimulation of hormone secretion by IFN-',/ has been observed both in vitro and in vivo. IFN--y induces the release of CRF from the hypothalamus (221,245), ACTH from the pituitary (42), and IFN-a induces the release of cortisol from the adrenal gland (393). These effects support a participation of IFN-~/ and IFN-a in the regulation of the neuroendocrine system. Pyrogenic effect. IFN-a induces fever (44) through direct action in hypothalamic target sites (see the General Discussion section). Somnogenic effect. Peripheral or central administration of IFN-a enhances slow-wave sleep in rabbits (47). Neurotoxic effects. In human, IFNs occur in low concentrations and when high doses of IFNs are administered, several adverse effects are induced in a variety of systems (see also the General Discussion section). Subjects receiving IFN therapy show several alterations in behavior and sleep patterns (3,92). These neurotoxic effects include fever, fatigue, anorexia, dizziness, impaired cognition, mood alterations and CNS depression (3, 92, 1421. Experiments in mice show that administration of rhlFN-o~ during the neonatal period results in decreased body and brain weights, decreased spontaneous activity levels, and an impaired retention of a learned behavior (327). In addition, peripheral administration of mouse IFN-a suppresses food intake and locomotor activity in mice (407), whereas ICV administration of rat IFN suppresses tbod intake in rats (366), but specificity of this effect requires further studies. TRANSFORMING GROWTH FACTORS (TGFsl

Nomenclature and Chemical Characteristics TGFs are polypeptides that have the ability to induce acute

phenotypic transformations in several normal cells (174,388). There are two molecular forms of TGFs: TGF-a which is composed of 50 amino acids (mol.wt. of approximately 6000) (69,174), and TGF-[3 which is a disulphide-linked homodimer constituted by two identical chains of 112 amino acids (mol.wt. of approximately 25,000) (105, 174. 300, 441). Three types of TGF-[3s have been identified: TGF-[31 (105,442). TGF-[32 (102,442), and TGF-133 (442,460). The C-terminal 112 amino acid segment of TGF-13s exhibits 70% to 80% sequence homology (102, 105,460). TGF-[3s have qualitatively similar biological actions. Synthesis Peripheral. TGF-c~ is synthesized and released by a variety of transformed and nontransformed cells (388). TGF-[3 is released from alpha granules of platelets (TGF-[31 is the major form) (442), activated macrophages (442), T-lymphocytes (233), and transformed cells (214). Central. Evidence shows that TGFs are produced in the CNS. TGF-a immunoreactive cell bodies (85) and TGF-a mRNA (260) have been identified in the rat brain. TGF-c~ mRNA has been detected in the rat developing hypothalamus (340) and mouse neurons from the striatum (193). TGF-a mRNA has also been detected in bovine neural retina (138). TGF-c~ immunoreactive fibers have been localized in the rodent globus pallidus (193) and in the human striatum (193); interestingly, the pattern of striatum TGF-a immunoreactivity appears lost in Huntington's disease (193), but the significance of this finding remains to be determined. In developing and adult brains, TGF-a-like immunoreactivity has been found in a subpopulation of glial cells (279). TGF-[3 is synthesized by normal (387) and neoplastic (82,494) CNS cells. In vitro studies have found that TGF-[3 secretion by glioma cells correlates with in vivo tumorigenicity (494). This may suggest a participation in the promotion of malignancy. TGF Receptors TGF-a binds to the epidermal growth factor (EGF) receptor with high affinity (69, 174, 442). Specific EGF receptors, which activate specific functions, are widely distributed in the CNS (203, 216, 237, 374, 492, 498). The receptor is a 170-185 KDa glycoprotein that presents four domains: an extracellular binding site, a hydrophobic transmembrane segment, a cytoplasmic domain which binds ATP, and a terminal cytoplasmic segment which undergoes phosphorylation (299). High density of TGF-a/EGF specific, high affinity receptors are present in bovine neural retina (138). EGF receptors are also present in approximately 79% of malignant gliomas (378) and 87% of meningiomas (378,380). TGF-13 does not bind to the EGF receptor. Cell plasma membrane receptors for TGF-[3 are ubiquitously expressed in various cell types. Three classes of TGF-[3 receptors with different structures have been identified (78): type I and II receptors bind TGF-[31 with higher affinity than TGF-[32; type III receptors bind TGF-131 and TGF-[32 with similar affinity (214). Biological Actions of TGFs Actions in the immune system. TGF-o~ is a mediator o1 inflammation (174). TGF-[3 controls proliferation, differentiation, and other functions of normal and neoplastic cells (441). TGF-13 is also a mediator of inflammation and repair (442), and a stimulator of angiogenesis (4421. It is proposed that TGF-[3 participates in the control of embryogenic development (214). Actions in the neta,ous system. TGF-a is about 40% homologous to EGF (69,298) and produces the same biological signals


in target cells as EGF (58,69); these signals are mediated through EGF receptor (58, 69, 198). Because of these properties, TGF-a may have similar effects in the CNS to those induced by EGF. EGF acts as a mitogen for glial cells (215, 216, 424, 493), and survival and neurotrophic (6, 72, 121, 237, 240, 242, 319, 320) as well as morphogenic (126,394) agent. EGF or TGF-o~ regulate CRF (283), LHRH (340) and growth hormone (74) secretion, and suppress gastric acid secretion (68, 181, 299, 434) and food intake (364) through a CNS modulation. EGF and TGF-a inhibit the expression of myelin basic protein (414)--a marker of oligodendrocyte maturation in the developing CNS--and enhance neuronal survival in multiple regions of the CNS (319) and neurite outgrowth in primary neural cultures from cerebral cortex (319). TGF-13 also exerts specific neurotrophic effects on subpopulations of dorsal root ganglium neurons (75). This effect by TGF-[3 appears to be partly mediated by promotion of nerve growth factor release (75) and is clearly distinct from the neurotrophic effect exerted by TGF-a (75). TGF-13 also stimulates DNA synthesis in short-term Schwann cell cultures, but inhibits DNA synthesis in long-term cultured Schwann cells and enteric glia (122). Two molecular forms of TGF-13, TGF-131 and TGF-132, are mitogenic for rat Schwann cells (382). In another study, TGF-131 was found to be a potent inhibitor of astrocyte growth in vitro (465); TGF-131 inhibited DNA synthesis induced by serum, and also inhibited the induction of glutamine synthetase activity--a marker of astrocyte differentiation by hydrocortisone (465). TGF-13 stimulates FSH secretion (214) and inhibits ACTH (140,212) suggesting a participation in the regulation of the neuroendocrine system. Preliminary studies have shown that ICV administration of TGF-13 does not affect food intake (368). THYMICPEPTIDES Chemical Characteristics This family of immunopeptides (280,379, 491) includes: thymopoietin (49 amino acids): thymosins a-I (28 amino acids), a-1 I (35 amino acids), 134 (43 amino acids), 138 (39 amino acids), 139 (41 amino acids), and 1310 (42 amino acids); thymulin (a zinccontaining nonapeptide); and thymic humoral factor (31 amino acids). Synthesis Peripheral. The thymus gland synthesizes and releases these immunopeptides (280, 379, 491). Central. Thymopoietin and thymosins have been detected in the CNS (188, 35 I, 379, 491). Thymosin-a 1 specifically immunoreacts with the astrocyte cell bodies, but not processes, in the normal human brain (450). Thymosin-al is present throughout the brain with highest concentrations in the arcuate nucleus and median eminence (188,351). This evidence may suggest that thymosin-al is synthesized in CNS components, but may also be taken up from the peripheral circulation through the median emi,nence--a CVO. Thymosin-134 has also been detected in rodent brain (192), and thymosin-134-immunoreactive cells in human brain have been identified as oligodendrocytes (95,450). Thymic Peptide Receptors A variety of cells display specific receptors for thymic peptides, but nature and regulation of these receptors in the CNS remain to be determined.

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primitive lymphocytes into immunologically competent Tcells (491 ). Actions in the nervous system. Evidence shows that these peptides may participate in neuromodulator and neuroendocrine functions (379,491). In initial studies, it was found that thymosin F5, a complex mixture of about 40 to 50 peptides from the thymus, increases secretion of ACTH (197,288,437), cortisol (197,288, 437), and 13-endorphin (197) in various species including the primate [for review on the effects of thymosin F5 on the neuroendocrine system see (188,189)]. Purified preparations of thymosins also affect the neuroendocrine system. Thymosin-al stimulates the release of ACTH (188) and corticosterone (189) after ICV administration. Thymosin-134, on the other hand, stimulates the release of LH-releasing hormone from the rat hypothalamus in vitro (377), and the release of LH in vivo (189). In electrophysiological experiments, ICV administration of thymic humoral factor decreased the PA-AH multiunit electrical activity and increased EEG synchronization (398). These effects may be related to thermoregulatory and sleep pattern modifications. PLATELETFACTOR4 (PF4) Chemical Characteristics, Synthesis and Receptors PF4 is a tetrameric peptide (mol.wt. of 7800) stored in the alpha granules of platelets (20,422,485). The human PF4 contains 70 amino acids (485). PF4 is released into the blood during platelet aggregation (422,485). Under some clinical conditions, e.g., Crohn's disease (which is accompanied by anorexia and body weight loss), a high plasma concentration of PF4 has been detected (422). To date, no evidence of CNS production of PF4 has been reported. Very little is known about PF4 receptors in the CNS. Biological Actions of PF4 Actions in the immune system. PF4 is a mediator in neutrophilplatelet interactions (20) and hence participates in acute inflammation. PF4 exhibits antiheparin activity (20,485), and a chemotactic effect on neutrophils, monocytes (20) and fibroblasts (411). It also inhibits angiogenesis (293). Actions in the ne~a,ous system. Outgrowth of retinal neurites evoked on substrata of PF4 has been reported (71 ). PF4 acts directly in the CNS to suppress food intake (364). ICV administration of PF4 (50-100 ng/rat) suppresses the nighttime food intake, whereas peripheral administration of PF4 in doses equivalent to or higher than those administered centrally has no effect on food intake (364). TUFI'SIN Chemical Characteristics. Synthesis and Receptors Tuftsin is a tetrapeptide (Thr-Lys-Pro-Arg) present in the CH 2 domain of the Fc fragment of the heavy chain of the IgG, leukokinin molecules (330, 421, 499). Tuftsin circulates in the blood and is cleaved by a spleen enzyme (330,421). It is only active as a tetrapeptide and when the spleen is removed, it remains inactive because it cannot set free from its carrier leukokinin (330). Tuftsin induces specific effects in a variety of cells. However, nature, regulation and signaling of tuftsin binding or receptor sites remain to be determined.

Biological Actions of Thymic Peptides

Biological Actions of Tuftsin

Actions in the immune system. Thymic peptides are essential to the development of the various subsets of T-lymphocytes (404,491). They control the proliferation and differentiation of

Actions in the immune system. Tuftsin activates all functions of phagocytic and granulocytic cells (phagocytosis, pinocytosis, motility, chemotaxis) (330,499), and influences antibody forma-

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tion (57, 330, 499). Tuftsin promotes antibacterial and tumoricidal activity of phagocytic cells and augments immunogenic function of macrophages (330,421). In vivo experiments have shown that tuftsin induces a strong antibacterial activity without apparent toxicity (156). Actions in the nervous system. In the CNS, tuftsin has been shown to: 1) stimulate hypothalamic hormone release in rats (311 ): 2) induce short-term antinociception when administered ICV (201). This effect is not affected by naloxone (201); 3) increase exploratory activity when administered ICV (201,410); 4) increase blood pressure when administered ICV (201); and 5) suppress food intake (363). ICV administration of tuftsin (150-1250 p,g/rat) suppresses the nighttime food intake, whereas daytime food intake increases (363); peripheral administration of higher doses to those administered centrally has no effect on food intake suggesting a direct action in the CNS (363). ICV administration of high doses of tuftsin or tuftsin analogues produces, in addition to food intake suppression, nonspecific behaviors such as jumping and barrel rotations (201,363). Since tuftsin induces IL-1 release (139), an involvement of IL-I in the food intake suppression by tuftsin (at low doses) is a plausible possibility. PLATELET-ACTIVATINGFACTOR(PAl) Chemical Characteristics PAF is an alkyl-ether phospholipid (1-0-alkyl-2-acetyl-snglycero-3-phosphocholine) mediator of inflammation (49,191). Synthesis Peripheral. PAF is produced by various cell types including platelets (49,191 ), polymorphonuclear leukocytes (49,191), monocytes/macrophages (49,191), endothelial cells (49, 59, 191, 205), and immune system cells (59,261). Central. PAF is synthesized by retinal (59) and brain cells (49, 464, 509) including neurons (512). Lipid extracts of bovine brain contain four species of PAF and ten acyl analogues of PAF (464). One species of PAF is found at concentrations of approximately 7.5 p,g/bovine brain (464). An acetyl hydrolase involved in PAF biosynthesis is present in high amounts in the rat brain (117a). Release of PAF in the Nervous System PAF is involved in the pathophysiology of a variety of conditions compromising the CNS including: traumatic brain injury (130); acute inflammation and allergies (49,205); arterial thrombosis (49), atherosclerosis (49) and postischemic disorders (49); endotoxic shock (49); and graft rejection (49). It is proposed that PAF antagonists may provide protection in restricting secondary brain damage following brain trauma or cerebral ischemia (155). In retinal cells, neurotransmitters (acetylcholine and dopamine) can induce PAF production (117a), but the consequences of this action are unclear. PAF Receptors High affinity binding sites for PAF with receptor characteristics have been found in the rat brain (464), in particular, in the cerebral cortex (18) and hypothalamus (l17a). However, nature, regulation and signaling mechanisms of these receptors are unknown. Biological Actions of PAF Actions in the immune system. PAF is a mediator of inflammatory and allergic reactions (49, 191,205). On monocytes/mac-

PLATA-SALAM,/~N

rophages (49,191), PAF modulates chemotaxis, aggregation, enhancement of cytotoxicity and immunoregulator synthesis and release. In addition, PAF modulates T- and B-cell functions (49), increases the response of lymphocytes to IL-2 (49), and increases suppressor cells (49) and natural killer activity (49). Actions in the nervous ,Lvstem. Effects on growth al,d differentiation. PAF induces morphological differentiation of cloned neuronal cell lines (49) and also has the ability to initiate neuronal gene expression (5). Neuromodulator 3, effects. Several neuromodulatory effects of PAF have been reported including: 1) an increase in the intracellular levels of free calcium ions in cloned neuronal cell lines (243) and in myenteric neurons (144). It is proposed that release of intracellular stores of calcium by PAF induces the release of acetylcholine and activation of calcium-dependent channels (1 44). Evidence also shows that PAF induces bronchoconstriction through activation of postganglionic parasympathetic nerves (261); 2) a modulation of the number of bet%-adrenergic receptors in rat cerebellum (49); 3) an induction of serotonin release (324); 4) a stimulation in the synthesis of prostaglandins and thromboxanes in various cell types including retina (59); 5) a dose-dependent inhibition of the electrophysiological responses elicited by brief light pulses on isolated retina (115); and 6) a rapid and transient receptor-specific activation of the proto-oncogenes c-fos and c-jun in SH-SY5Y neuroblastoma cells (443). This effect may indicate a participation of PAF in phenotypic changes within the nervous system. Effects on the neuroendocrine system. PAF stimulates the release of CRF from the hypothalamus (27,28); this effect is mediated by calcium influx and phospholipase-A z activation (27). PAF also inhibits LHRH and somatostatin release from the median eminence (224), and induces the release of ACTH (28), growth hormone (117a) and prolactin (117a) from the pituitary gland. Thus, PAF may participate in the activation of the neuroendocrine system during immune responses. PAF and feeding regulation. Evidence shows that PAF suppresses food intake by direct action in the CNS (363). ICV administration of PAF (10-500 rig/rat) suppresses nighttime food intake. whereas peripheral administration of PAF in doses higher than those administered centrally has no effect on food intake (363). PAF bTteractions With Other Immunoregulators IL- I and TNF induce the synthesis and release of PAF (60,65) (see the General Discussion section). IL-I promotes the conversion of the biological inactive lyso-PAF to the bioactive PAF by an acetylation reaction (60). Thus, some of the effects of IL-I and TNF may be indirect through the induction of PAF. OTHER IMMUNOREGULATORS Other immunoregulators may also act as neuroimmunoregulators. These include interleukins 3, 4, 5, 7, and 8, neuroleukin, and colony-stimulating factors. hzterleukin-3 (IL-3 ) IL-3 (commonly referred to as multicolony-stimulating factor) is a polypeptide of 129 amino acids (265, 315, 362). Human and murine IL-3 are 29% homologous (162,315), but they have a similar spectrum of biological activity (315). IL-3 is produced by T-lymphocytes, monocytes/macrophages (22. 107,315). and brain astrocytes (136, 151,372). IL-3 induces the proliferation and differentiation of immature lymphocytes (22, 107, 315, 362, 453) and pluripotent (multilineage) bone marrow stem cells (107,114) (Fig. 3). In the CNS, IL-3 has the ability to induce microglial


proliferation (154,372) suggesting a participation in brain immune and inflammatory responses. IL-3 is also atrophic factor for rodent central cholinergic neurons as demonstrated in vitro and in vivo (228). In this study, IL-3 enhanced neurite outgrowth and increased choline acetyltransferase activity without affecting somatostatin release or the activities of the glutamic acid decarboxylase and a phosphodiesterase (228). This evidence may suggest specificity on cholinergic processes, but its significance remains to be determined.

hlterleukin-4 (IL-4) IL-4 (also called B-cell stimulating factor-1 or BSF-I) is a 15 KDa polypeptide (62,265,362,453). IL-4 is produced by T-lymphocytes, macrophages (certain cell lines) and mast cells (141). IL-4 induces the activation, growth and differentiation of B-cells (114, 176, 343, 362, 453) (Fig. 3). IL-4 is also a growth factor for resting T-cells (107,114).

buerleukin-5 (1L-5 ) IL-5 (also called T-cell replacing factor or TRF) is a 13 KDa polypeptide in its mature form (9, 62, 236, 455). Human and murine IL-5 are 70% homologous (9). IL-5 is produced by T-lymphocytes (141, 343, 455). IL-5 induces the activation, growth and differentiation of B-cells (176,343) (Fig. 3), and also activates differentiation of eosinophils (141).

lnterleukin-7 (IL-7) IL-7 is a 25 KDa glycoprotein produced by bone marrow stromal cells (335), thymus (312), and spleen (312). IL-7 induces proliferation of B-cell precursors (62, 335, 349) and also affects T-cells (312).

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TABLE 1 PARTIALLISTOF NEUROREGULATORS(NEUROTRANSMITTERS. NEUROMODULATORSAND NEUROPEPTIDES)THAT HAVEBEEN SHOWN TO AFFECTIMMUNOLOGICALFUNCTIONS Classical Neurotransmitters* Epinephrine Norepinephrine Dopamine Serotonin Acetylcholine Histamine

Neurohypophyseal Peptides¶ Vasopressin Oxytocin

Gut-brain Peptides# Cholecystokinin Insulin Somatostatin Opioid Peptidest Bombesin c~-, [3-. -,/-Endorphins Vasoactive intestinal Leu-enkephalin peptide Met-enkephalin Neurotensin Substance P Hypothalamic Peptides~ Leu-enkephalin Gonadotropin-releasing hormone Met-enkephalin Somatostatin Pituitary Peptides§ Thyrotropin Adrenocorticotropic hormone Growth hormone Prolactin Gonadotropic hormones Melanocyte-stimulating hormone [3-Endorphin

Other Peptides** Calcitonin Calcitonin gene-related peptide Angiotensin II Insulin-like growth factor-I Nerve growth factor

*: 41. 187,287,483 t: 41, 70. 134, 135,219, 220, 275,287, 297,427,488,496, 504 ~: 41, 173. 284, 339, 360, 444 §: 41. 123, 248, 339, 429. 488 ¶: 41,496 #: 41.96, 234, 235,263, 277, 284, 339, 345. 360,449, 496 **: 2, 41,241,360, 415,462

h,terleukin-8 (1L-8) IL-8 is a 72 amino acid peptide produced in monocytes (182, 257, 511), lymphocytes (257), vascular endothelial cells (168), and other cells (10). IL-8 promotes chemotaxis of leukocytes (448,511) and T-lymphocytes (257); it also inhibits neutrophil adhesion to cytokine-activated endothelium (168). IL-8 presents a 42% homology with PF4 at the N-terminal sequence (511). At present the effects of IL-4, IL-5, IL-7, and IL-8 in the CNS are unknown. However, because of their immunological actions, these interleukins may have similar effects in the CNS to those induced by IL-I, IL-2, or IL-6, but this possibility remains to be determined.

Neuroleukin (NLK) NLK is a 56 KDa protein produced by T-lymphocytes (185). NLK stimulates immunoglobulin production by B-lymphocytes (185), and acts as neurotrophic factor for spinal and sensory neurons (186). NLK has been recognized to be the glycolytic enzyme, phosphoglucose isomerase (77,133), but the relationship between this and other activities is poorly understood.

Colony-Stimulating Factors ( CSFas ) CSFas are produced by macrophages (macrophage-CSFa), granulocytes (granulocyte-CSFa) (114,420), and activated T-lymphocytes (107). CSFas stimulate hematopoiesis (114). Human astroglial tumor cells lines (U87MG and U373MG) can be induced to produce granulocyte-CSFa and granulocyte-macrophage CSFa following exposure to I L - l a and IL-I[3 (470). This is indicated by

increases in CSFas mRNAs (470). CSFas may also act as neuroregulators of immunologic origin because of a partial homology with IL-6 (206) and overlapping with IL-3 biological activities (107). NEUROREGULATORS(NEUROTRANSMITTERS. NEUROMODULATORSAND NEUROPEPTIDESI AS IMMUNOREGULATORS A variety of neuroregulators have been shown to act as immunoregulators. These neuroregulator-immunoregulators are listed in Table 1 and each one exerts specific immunoregulatory actions through specific receptors on immune system cells. Since the effects of these neuroregulators on the immune system have been described in detail in numerous reports, the discussion presented here will briefly summarize the main findings. Neuroregulatorimmunoregulators include classical neurotransmitters, proopiomelanocortin derivatives, hypothalamic and pituitary peptides, gut-brain peptides, and other peptides.

Classical Neurotransmitters Epinephrine and norepinephrine, and serotonin induce immunosuppression (187, 287, 483); dopamine and acetylcholine are immunostimulating neurotransmitters (187,287).

Proopiomelanocortin Derivatives These include: a) ACTH which is synthesized in macrophages (488) and lymphocytes (287), and modulates B-cell proliferation

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PLATA-SALAM/~N

and antibody production (220), and macrophage and T-cell functions (220): and b) opiates (alpha-, beta-, and gamma-endorphins, and Leu- and Met-enkephalin) and alpha-MSH which are synthesized in macrophages (275,488) and lymphocytes (427), and induce a variety of effects on the immune system (70, 134, 135, 219. 297,488,496, 504).

Hypothalamic and PituimtT Peptides These include: a) thyrotropin which is synthesized in lymphocytes (429), and enhances antibody production (248); b) growth hormone which is synthesized in lymphocytes and leukocytes (488), and modulates proliferation and differentiation of T-lymphocytes (488); c) somatostatin which is produced by a variety of immune system cells (173,284), and induces a wide spectrum of immunomodulatory influences (360,444); d) FSH and LH which are synthesized in immune system ce~s (488); e) prolactin which augments various immune system responses (123); and f) vasopressin and oxytocin which induce various immunomodulating actions (496).

Gut-Brain Peptides These include: a) cholecystokinin which has immunomodulatory actions on monocytes (496); b) insulin which also exerts specific effects (449); c) somatostatin (see above); d) bombesin which is synthesized in macrophages; e) VIP which is synthesized in mast cells and platelets (284). VIP activates cAMP production in lymphocytes (96), and has effects on leukocyte functions (345,360); f) neurotensin which increases phagocytosis ability of monocytes, and evokes release of histamine from mast cells (360): and g) substance P which increases T-lymphocyte proliferation (359), and stimulates monocyte chemotaxis (360) and other leukocyte functions (360). Substance P levels increase in inflamed tissues and it is proposed that substance P participates in neurogenic inflammation following its release from injured sensory nerves (263). Substance P also induces the release of IL-1, TNF, and IL-6 from monocytes (235,277), and potentiates IL-I actions (234).

Other Peptides These include: a) calcitonin which is synthesized in immune system cells (241); b) calcitonin gene-related peptide which acts as a mediator of leukocyte functions (360): c) angiotensin II which induces various effects on macrophages and T-lymphocytes (415,462); d) insulin-like growth factor-I which is synthesized in lymphocytes; and e) nerve growth factor which enhances sympathetic innervation of immunocompetent organs and induces activation of plaque-forming and lymphocyte blast transformation (2). These neuroregulators synthesized and released by immune system cells may act as autocrine and/or paracrine factors to affect immunological functions, and as endocrine factors affecting distant target organs (Fig. 2), GENERAL DISCUSSION IMMUNOREGULATORSANDTHE NERVOUSSYSTEM: AN INTEGRATIVEVIEW

Communication Between the Nervous and the bnmune Systems A reciprocal communication between the nervous and the immune systems is organized through various interrelated levels (Fig. 1). Communication from the nervous to the immune system includes humoral and neuroanatomical pathways (Fig. 1). Evi-

dence for this neuroimmune communication include: conditioning of immune responses (120); alterations of immune functions in the presence of neuroregulators (Table 1) and endogenous factors released during stress (97, 120, 323); and alterations of immune responses after lesions or electrical stimulation of specific CNS sites (120). Communication from the immune to the nervous system is dependent on immunoregulators released by activated immune or CNS cells (see the General Description section). These immunoregulators will induce a variety of neurochemical, neurophysiological or neuropathophysiological, neuroendocrinological, and neurotoxicological responses.

bnmunoregulators and Growth-Promoting Activity in the Nervous System Various immunoregulators (e.g., IL-I, IL-6, TNF, BCGF) have mitogenic effects on astrocytes. This biological action supports a role of immunoregulators in CNS normal development, wound healing, and development of reactive gliosis (e.g., in multiple sclerosis). In addition, the increase of NGF synthesis induced by IL-I and IL-6 supports their neurotrophic effect (153, 157, 272, 346). Evidence suggests that during development, immunoregulators secreted in the nervous system may modulate CNS intercellular communication (neuron-glia and glia-glia interactions) influencing mitogenesis, myelination, and neurite outgrowth ( 171 ).

hnmunoregulators and the Neuroendocrine System Activation of the immune system is frequently accompanied by activation of the neuroendocrine system. Evidence supports a feedback loop involving immunoregulators and the neuroendocrine system--hypothalamus, pituitary and adrenal glands (19, 26, 29, 31, 34, 399, 469, 471) [for an integrative review see (17)]. II-1, TNF, IFN-'y, PAF, and other immunoregulators induce the synthesis and release of CRF from the hypothalamus (27, 28.34, 64, 221,469), ACTH from the pituitary (19, 29, 31, 34), and corticosterone from the adrenal glands (31,34). The increase in serum corticosterone in turn inhibits the synthesis and release of IL-1 and TNF (61). This inhibition of immunoregulator production may participate in the immunosuppressionobserved during corticosteroid treatment. Another aspect of the interaction between immunoregulators and the neuroendocrine system is the reciprocal dynamic regulation, i.e., ACTH, thyrotropin, and other pituitary peptides can bind to lymphocytes and modulate specific functions, whereas lymphocytes can also synthesize and release ACTH, thyrotropin, and gonadotropins in response to immunological stimuli (see the Neuroregulators as lmmunoregulators section).

bnmunoregulators and Fever Immunoregulators induce fever by direct action in hypothalamic target sites. IL-la, IL-l[3, and TNF induce fever, dose dependently, when administered ICV in conscious rats (36, 99,395) and rabbits (98, 195,217,316, 317). Unilateral microinjection of IL-I into the anterior hypothalamus also induce fever. OVLT is involved in the febrile response to immunoregulators (445); electrolytic lesions of the OVLT in guinea pig (44) attenuate the fever-inducing effect of peripherally administered IL-113, TNF-a, and IFN-a2. This suggests that peripheral immunoregulators induce fever by a direct interaction with the OVLT, a CVO in close contact with the preoptic area-anterior hypothalamus (PA-AH) which is considered as a primary (217), but not exclusive (484),


site for thermoregulation. Peripheral administration of immunoregulators also induce fever in human (1841. Increased plasma concentrations of immunoregulators in patients with various pathological processes (see sections on IL-I and TNF) may be part of the signals inducing fever during these conditions. Evidence supports that prostaglandins synthesized in the CNS are the mediators of fever induced by immunoregulators since: 1) IL-Ic~ and IL-113 increase PGE, production in rat astrocytes (194,230) by a protein kinase C dependent mechanism (194). IL-1 also increases PGE,_ production in the PA-AH (4251. It is also proposed that prostaglandins released from the OVLT can diffuse and reach the PA-AH to induce fever (446): 2) in the PA-AH, microelectrophoretic application of rhlL-1 in vivo (211) or application by superfusion in brain slices (333) inhibits the warm-sensitive and excites the cold-sensitive neurons; these effects are blocked by sodium salicylate (211,333). Similar effects have been observed with rhlFN-a (332); 3) sodium salicylate and indomethacin (both inhibitors of prostaglandin synthesis) suppress the fever (195) and hypothalamic production of prostaglandins (425) induced by IL-I; 4) the rate of hypothalamic PGE2 release is correlated with the intensity of fever (425); 5) peripheral administration of IL-I increases levels of PGE 2 in the CSF (83) and ICV administration of PGE 2 produces a dose-dependent fever (316); and 6) prostaglandins participate in other alterations of vital functions induced during fever (383). It is important to note that fever is associated with increase in metabolic rate and brown adipose tissue activity, and immunoregulators can also stimulate thermogenesis by a direct CNS action (395). Kawasaki et al. (232), have proposed that the endotoxin-induced fever involves three stages: 1) an early effect on the PA-AH within one hour after endotoxin administration; 2) a delayed endotoxin-induced TNF-o~ release from various cell types resulting in the activation of the PA-AH by TNF-a at about 1.5 h after endotoxin administration; and 3) a TNF-a induced production of IL-I which will elicit the late-peak fever at about 3.5 h after endotoxin administration.

bnmunoregulators and Sleep Immunoregulators participating in immune responses promote sleep. This is evident during infectious diseases that are often accompanied by increased sleep--considered an essential component of the host recovery from infection. Peripheral or central administration of bacterial products (muramyl peptides and endotoxin) (47, 305,484) and immunoregulators (IL-I, TNF, IFN-a, and VIP) enhance slow-wave sleep (246, 247, 417, 463, 484) [see (47)]. Evidence also suggests a physiological participation of IL-1 in human sleep since plasma levels of IL-I peak at the onset of slow-wave sleep (47,314). In addition, IL-l-like activity in the CSF of cats was higher during sleep than during waking (282). Prostaglandin-dependent mechanisms are involved, at least in part, in the somnogenic effect induced by bacterial products (506) and by immunoregulators (246,506). It should be noted, however, that the somnogenic effect of immunoregulators occur separately from their fever-inducing effect (246,484). This is supported by the fact that fever induced by immunoregulators can be blocked with antipyretics without affecting the sleep pattern (246).

bnmunoregulators and Feeding Regulation Acute and chronic pathological processes are accompanied by food intake suppression. A variety of immunoregulators act directly in the CNS to suppress food intake [for review see (366)]. Several lines of evidence suggest the specificity of immunoregulators inducing food intake suppression. These include: 1) food intake is suppressed only during the nighttime (i.e., during the

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period of physiologic hyperphagia in the rat), while it is increased during the daytime (363, 364, 368); 2) rhIL-113 does not affect dipsogenesis induced by angiotensin II when administered ICV and when the feeding suppressive effect is stronger (368). This evidence together with decreases in food-to-water intake ratios (368) and increases in water intake accompanying food intake suppression (129) suggest behavioral specificity; 3) peripheral administration (IV, IP or SC) of high doses of immunoregulators suppress food intake (146, 200, 286, 313, 322, 347, 472, 473). However, peripheral administration of immunoregulators in doses equivalent to or moderately higher than those administered centrally have no effect on food intake (363, 364, 368). In addition, ICV administration of rhIL-113 suppresses food intake with potency greater than I000 times that of peripheral administration of rhIL-113 increasing CRF release from the hypothalamus (399) and ACTH and corticosterone blood levels (31). This evidence indicates an effect in the CNS; 4) potency suppressing food intake is different among immunoregulators (363,364, 368). For example, rhlL-113 requires much lower doses than rhIL-6 to suppress food intake after ICV microinfusion (363): and 5) the decrease of food intake by immunoregulators is not related to a fever-inducing effect (285, 313, 363, 368). This is consistent with two clinical observations: I) patients with fever present appetite suppression regardless of antipyretic therapy; and 2) during infection, food intake is suppressed even when metabolic rate rises 10% to 13% for each degree centigrade increase in body temperature (118). Various immunoregulators act directly and specifically on hypothalamic feeding-associated sites to suppress food intake (368). Electrophysiological studies show that IL-I- and TNF-e~-induced feeding suppression involves inhibition of glucose-sensitive neurons in the LHA (considered a "hunger center"). The feeding patterns induced by various immunoregulators are consistent with this action mechanism on LHA (368). Electrophysiological studies also show that 1FN-a-induced feeding suppression may involve excitation of glucose-sensitive neurons in the VMH (considered a "'satiety center") (334). Immunoregulators also decrease gastric emptying and motility (479), increase endogenous factors such as glucagon (109), insulin (109), and CRF (26, 399, 469), and induce sleep (see the Immunoregulators and Sleep section). These effects may also participate in the food intake suppression by immunoregulators since all of them have been shown to suppress food intake (318, 367, 369, 473, 502). A restriction of the intake of nutrients (which are essential to the growth and survival of pathogenic organisms) and a redistribution of nutrients (326) might be part of the biological roles of the temporal food intake suppression during host recovery from infection. Production of prostaglandins, in particular PGE 2, appears to be necessary for IL-1 to induce food intake suppression. This is based on the observations that prostaglandin synthesis inhibitors, such as ibuprofen (200) and indomethacin (472), suppress or block the food intake suppression by IL-I. Feeding on fish oil, a diet decreasing production of immunoregulators (125), also diminishes the food intake suppressive effect of IL-1 (200). This indicates that dietary factors modify the production and activity of immunoregulators. However, additional studies are required to determine the effects of other macro- and micro-nutrients on the release of immunoregulators during acute and chronic diseases. The potential clinical implications of these observations are enormous, since by nutritional modifications, there is the possibility to prevent the suppression of food intake by immunoregulators during a critical time in a particular disease.

hnportance of the Amounts of hnmunoregulators Administered The concentration of immunoregulators in body fluids is low under basal conditions (84, 301, 338. 376, 454, 466). It is diffi-

200

cult to know how much of the immunoregulators used in vivo studies (peripheral and central administration) mimic endogenous (circulating and CSF) immunoregulators in timing and achievement of local concentrations of these factors in brain target sites. It is clear, however, that the range in the effective amounts of exogenous immunoregulators is within the values observed in various conditions. For example, under basal conditions, human body fluids have little IL-6 detectable by various bioassay systems (199, 376, 438, 456). In acute and chronic pathological processes, however, high levels of IL-6 can be present. High levels of CSF IL-6 (up to 500 ng/ml) have been detected in acute bacterial meningitis (199), endotoxemia (438), and in the acute phase response in severe burns (338). The effects of IL-6 in the CNS have been demonstrated in vitro and in vivo by lower or equivalent concentrations to those observed in these clinical conditions. IL-6 is a neurotrophic factor for cholinergic neurons at concentrations of 5-50 ng/ml (190), induces pyrogenesis at 50100 ng/kg (313,376), suppresses food intake at 15--60 ng/rat when administered ICV (363), and modulates the neuroendocrine system (hormone release from the anterior pituitary gland) at picomolar and similar concentrations to those affecting B-cells in a specific manner (329, 438, 500, 505). Thus, the doses of IL-6 administered in vitro and in vivo are not out of the pathophysiological range observed in some conditions. For simplicity, IL-6 was considered as example, but the same is applicable to other immunoregulators. Under basal conditions, CSF has little IL-1 detectable (84,454): CSF levels of IL-I increase to over 100 ng/ml after ICV administration of endotoxin (84). IL-113 increases CRF secretion from rat hypothalamus in vitro at 1-100 ng/ml (64,469), and ACTH from the pituitary gland in vivo at 30 ng/rat when administered ICV (17). Other studies in culture also show that the effects of IL-1 on pituitary hormone release occur at concentrations within the range of IL-I in serum (29). Following ICV administration, IL-I[3 suppresses food intake at 1-13 ng/rat (368), induces fever at 50 ng/animal (417). It is important to note, however, that insufficient evidence is available to establish any conclusion regarding the relationship between immunoregulator concentrations in body fluids and pathophysiological processes. On the other hand, treatments using high doses of immunoregulators--such as the adoptive immunotherapy for cancer (104,306)--are merely pharmacological and are consistently accompanied by a variety of neurotoxic effects (see below and the IL-2 section).

Multi-hnmunoregulatot3, blteraction lmmunoregulator production occurs in a "cascade" pattern. Tuftsin induces release of IL-1 and TNF-a (499). TNF-e~ induces the synthesis and release of IL-1 (33, 38, 110, 139, 337), IL-6 (376,456), and IL-8 (448). IL-1 induces the synthesis and release of IL-2, IL-3, IL-4, IL-6, IL-8, and CSFas (11 I, 112. 448,476, 477). IL-2 induces the synthesis and release of TNF and IFN-~/ (54). IL-I and TNF induce the synthesis and release of PAF (60,65). PAF induces the synthesis and release of IL-I and TNF (49), and the release of PF4 (440). Thus, IL-2, IL-3, IL-4, IL-6, CSFas, and PAF are mediators involved in a variety of immune, endocrine and CNS responses elicited by IL-I. This evidence indicates a multi-immunoregulatory interaction affecting CNS functions with an operation in a multilayered pathway. This pathway might have a final common messenger(s) such as prostaglandins, since as described throughout the text, immunoregulators affect specific CNS functions through prostaglandin-dependent mechanisms. The multi-immunoregulatory interaction also indicates that immunoregulators exhibit considerable overlap in their biological

PLATA-SALAM,~N

activities (343), and that caution is essential in interpreting the results of studies where single immunoregulators are used. A more complex interaction is evident with the action of inhibitor molecules. For example, a-MSH inhibits IL-I and TNF-cx inducible biological responses such as fever (100,389); a-MSH may contribute to the limitation of the rise in body temperature during fever (416). Centrally and peripherally administered (x-MSH acts as an antipyretic agent (101,209) and hypothalamic concentration of o~-MSH increases during fever (209). Thus, an interaction between immunoregulators and endogenous inhibitor molecules may be operative during specific conditions.

hnmunoregulators and Antigen E.~pression in the Nervous System Immunoregulators modulate antigen expression in the CNS. In the absence of immunoregulators, cells of the CNS express very low levels of major histocompatibility complex (MHC) antigens [see (495)]. The human MHC, called HLA (human leukocyte antigen) complex consists of the polymorphic membrane glycoproteins, the class I molecules (HLA-A, HLA-B, and HLA-C), and the class II molecules (HLA-DP, HLA-DQ, and HLA-DR) which determine the presentation of antigen for T-lymphocyte binding (244). MHC class I and class 1I antigens are absent in neurons (495), astrocytes (495), oligodendrocytes (495), and choroid plexus cells (495), while they are present in microglial cells (281,495). The MHC class I1 antigens are also expressed in normal brain macrophages (281) and endothelial cells (281) on white and gray matter samples. In the presence of IFN-"/ and TNF-o~, neurons (495) and oligodendrocytes (302,495) express MHC class I antigens, while astrocytes (15,258, 302, 495) and choroid plexus cells (495) express MHC class I and class I1 antigens. This modulation of antigenic determinants by immunoregulators is involved in the development of intracerebral immune responses. This also indicates that the CNS is not an immunologically privileged organ as traditionally has been thought. In human astrocytes, immunoregulators (IL-1, TNF-~x, IFN-~/, lymphotoxin) (158) can induce the expression of intercellular adhesion molecule l - - a molecule required for antigen presentation reactions dependent upon the expression of the MHC class II antigens (158). Expression of HLA molecules in the CNS also participates in autoimmune processes of the nervous system. For example, IFN-~ and HLA-DR antigen have been detected on astrocytes at the edge of active chronic multiple sclerosis lesions (468). HLA-DR-positive glial cells have also been shown surrounding metastatic tissue (150), gliomas (253), and in human immunodeficiency virus-infected CNS cells (390). MHC class II immunoreactive cells also proliferate in the gray matter of cerebral cortex in AD patients [for review see (390)]. It has also been determined that brain injury associated with intracerebral transplantation induces enhanced MHC class II antigen expression in brain macrophages and perivascular and parenchymal microglia adjacent to the implants (371). It is important to note that the CNS also contains inhibitory substances e.g., NE (159,160), IFN-a (15) and IFN-13 (15) that prevent the expression of MHC class II antigens on astrocytes in response to IFN-'y.

Immunoregulators and Clinical Medicine Acute and chronic pathological processes stimulate the synthesis and release of immunoregulators. Cooperation of immunoregulators (immunoregulatory network, Fig. 3) is essential in the coordination of immune and other host responses to acute and chronic disease. Immunoregulator production, release, and activity are tightly regulated. Insufficient (30, 184, 231, 267, 276,


201

325, 342, 418) or excessive (21, 32, 38, 110, 111, 303, 321) expression of a particular or various immunoregulators may contribute to pathological processes. In some instances, the pleiotropic activities of immunoregulators are reflected in responses of the entire organism. The presence of immunoregulators in the CNS is the result of local synthesis and uptake from the peripheral circulation (see the General Description section). For example, lipopolysaccharideand neurotropic virus-stimulated astrocytes produce IL-1, IL-6, TNF, and IFNs, and CSF concentrations of immunoregulators increase during peripheral pathological processes (see the IL-1, IL-6, and TNF sections). IL-1 synthesized by CNS components (see the IL-1 section) may activate T-cells which normally may cross the BBB and CVOs (451,489, 490). Activated T-cells can interact with brain cells (489,490), and produce and release immunoregulators including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF, and IFN-3' (114, 176, 343), Data obtained in experimental allergic encephalomyelitis also suggest that retrograde axonal signals from the peripheral nerves may alter the immune response within the CNS (289). Evidence above mentioned indicates that immune surveillance in the CNS occurs during acute and chronic diseases (inflammatory and malignant processes) of the nervous system and/or peripheral organs. The purpose of the immune activation will be the immune-mediated elimination of infectious agents, or the response to foreign agents, autoimmune processes, tissue damage or proliferation, in an attempt to protect the host. At the same time, however, monitoring of immunoregulators by the CNS induces a variety of neurological effects--such as lethargy, somnolence and sleep changes, decreased social interaction, fever, food intake suppression, and body weight loss--which frequently accompany acute and chronic diseases. While neurological manifestations are widely reported, little information is available to understand the basic mechanisms and significance.

hnmunoregulators and Clinical Therapeutics For immunoregulators (immunostimulating or immunorestoring) many potential therapeutic applications exist. The broad range of immune activities of TNF, IL-1, IL-2, IL-6, IFNs, thymic

peptides, CSFas, and phospholipid analogues of PAF may provide a therapeutic alternative in cancer (48, 114, 139, 204), viral (405) and autoimmune diseases (114), and as replacement therapy in immunoregulator deficiencies (54,202). IL-2 has been extensively used in adoptive immunotherapy (see the IL-2 section). IL-I may be appropriate as adjuvant (a substance that promotes the body's natural defense mechanisms) for cancer therapy (139). TNF mediates tumor necrosis reducing the tumor size (11). Immunoregulators, however, occur endogenously in low concentrations (84, 199, 376, 438,454, 456, 466) and when high doses of these substances--required to achieve the therapeutic goal--are administered, a variety of hematotoxic, nephrotoxic, hepatotoxic, cardiotoxic, and neurotoxic effects are induced (12, 142,474). Analysis of immunoregulator levels in biological fluids including CSF may be diagnostic of certain diseases, or may indicate the activity of a disease process. It might also serve as criterion of therapeutic efficacy. Understanding of the kinetics and degree of tolerance might also optimize therapeutic efficacy and minimize toxicity; for example, effects in the CNS and other systems observed after initial administration of TNF are normalized with continued administration of the same dose (149, 292, 357).

Future Directions To increase our understanding of the biological roles of immunoregulators in the CNS, the following aspects should be elucidated: 1) structure and properties of immunoregulator receptors in the CNS, their regulation, and molecular events and second-third messengers following immunoregulator-receptor interaction; 2) mechanisms of synthesis, processing and release of immunoregulators in the CNS; and 3) role of MHC antigens in the production and action of immunoregulators in the CNS. Research on immunoregulators in the nervous system is essential to understand the neurophysiological or neuropathophysiological significance of these factors, and their participation in the reciprocal neuroendocrine-immune communication. These studies may be essential to devise effective and less toxic regimens for prophylaxis and treatment of diseases involving the nervous system and/or peripheral organs.

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IMMUNOREGULATORS

IN T H E N E R V O U S S Y S T E M

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214

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PLATA-SALAM,~N

580.

581.

582.

583.

584.

585.

586.

587.

588.

589.

590.

591.

592.

593.

594.

595.

596.

597.

598. 599.

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Sarcoidosis in the nervous system.

Breathing and the nervous system.

Ethanol and the nervous system.

Popular Physiology.-The Nervous System.

Macrophages and the nervous system.

Acupuncture and the nervous system.

Sarcoid of the nervous system.

Diseases of the Nervous System.

Assessment of the nervous system.

MeCP2 in the enteric nervous system.

Roles of kinins in the nervous system.

The Central Nervous System in Addisonian Anæmia.

Views on regeneration in the nervous system.

The gastropod nervous system in metamorphosis.

Varicella Zoster Virus in the Nervous System.

GABA-receptors in the vertebrate nervous system.

Pain mechanism in the central nervous system.

Molecular motors in the nervous system.

Letter: Plasticity in the nervous system.

Imidazoline receptors in the nervous system.

Sexual dimorphism in the vertebrate nervous system.

BK Channels in the Central Nervous System.

Proceedings: Intravascular coagulation in the nervous system.

Circadian pacemakers in the nervous system.