Neuroendocrine peptide hormones and their receptors in the immune system: production, processing and action

Recent findings indicate that the immune and neuroendocrine systems interact and modulate one another functionally. The mechanism for this seems to be that the 2 systems share a set of receptors and ligands (hormones). Cells of the immune system are able to synthesize neuroendocrine peptide hormones which are biologically active and produced in physiologically significant quantities. Furthermore, leukocytes possess functional receptors for these same neuroendocrine hormones which will specifically modulate immune responses. The structural and functional evidence for these interactions is reviewed and discussed in the context of a bidirectional regulatory circuit between the immune and neuroendocrine systems.     

Neuropeptides as signal molecules in common with leukocytes and the hypothalamic-pituitary-adrenal axis

There exists a bidirectional regulatory circuit between the nervous and immune systems. This regulation has been shown to be mediated in part through neuroendocrine hormones and cytokines. Both systems have receptors for both types of signal molecules. The nervous system has receptors for cytokines and it also synthesizes cytokines. The immune system synthesizes and responds to cytokines. So, it is not too far-fetched to believe that neuroendocrine peptide hormones could bind to leukocytes and modulate immune functions. However, it is not widely known that the immune system also synthesizes functional, neuropeptide hormones. This will be discussed in this paper citing a plethora of evidence. The aim of this paper is to summarize this evidence by using three neuropeptides that are synthesized by leukocytes and modulate immune functions as examples; corticotropin (ACTH), endorphin (END), and corticotropin releasing factor (CRF). The production and action of these three neuropeptides in the immune system will be explained. Finally, the potential physiological role of leukocyte-derived ACTH, END, and CRF in inflammation as a localized hypothalamic-pituitary-like axis is discussed.     

Evidence of conserved neuroendocrine interactions in the thymus: intrathymic expression of neuropeptides in mammalian and non-mammalian vertebrates

The function of lymphoid organs and immune cells is often modulated by hormones, steroids and neuropeptides produced by the neuroendocrine and immune systems. The thymus intrinsically produces these factors and a comparative analysis of the expression of neuropeptides in the thymus of different species would highlight the evolutionary importance of neuroendocrine interaction in T cell development. In this review, we highlight the evidence which describes the intrathymic expression and function of various neuropeptides and their receptors, in particular somatostatin, substance P, vasointestinal polypeptide, calcitonin gene-related peptide and neuropeptide Y, in mammals (human, rodent) and non-mammals (avian, amphibian and teleost), and conclude that neuropeptides play a conserved role in vertebrate thymocyte development.     

Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep

This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system's ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep.     

Anti-inflammatory neuropeptides: a new class of endogenous immunoregulatory agents

Resolution of inflammation and induction of immune tolerance are essential to stabilize immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure the re-establishment of immune homeostasis and maintenance of tolerance. The identification of endogenous factors that regulate these processes is crucial for the development of new therapies for inflammatory/autoimmune conditions. Neuropeptides produced during an ongoing inflammatory response emerged as endogenous anti-inflammatory agents that participate in processes leading to the resolution of inflammation and maintenance of tolerance. Anti-inflammatory neuropeptides and hormones such as vasoactive intestinal peptide, urocortin, adrenomedullin, melanocyte stimulating hormone, ghrelin, and cortistatin have beneficial effects in a variety of experimental inflammatory and autoimmune models. Their therapeutic effect has been attributed to their capacity to downregulate innate immunity, to inhibit antigen-specific T_H1-driven responses, and to generate regulatory T cells. Finally, some of these neuropeptides have been identified as mediators of innate defense acting as natural antimicrobial peptides. Here we present the research findings in the neuropeptide immunoregulatory field, and examine possible therapies based on anti-inflammatory neuropeptides and hormones as a new pharmacologic platform.     

The relationship between interleukin-6 and herpes simplex virus type 1: implications for behavior and immunopathology.

Cytokines are hormones once thought to be restricted to the immune system produced solely by hematopoietic-derived cells and acting on receptors expressed by cells of the immune system. However, it is now clear that many cytokines are produced not only by lymphocytes, monocytes, granulocytes, and dendritic cells but are also synthesized by cells outside the realm of the immune system in response to stimuli that may not be associated with immune homeostasis. In fact, there is evidence supporting a role of selected cytokines modifying behavior and neuroendocrine function. Recently, a potential relationship between the cytokine interleukin (IL)-6 and herpes simplex virus type 1 (HSV-1) reactivation has been found. This article discusses the relevance of these findings and considers the potential impact that HSV-1 infection has on behavior and chronic inflammatory processes that can occur in the nervous system during "latent" virus infection as a result of chronic IL-6 expression.     

Regulation of VIP production and secretion by murine lymphocytes.

Vasoactive intestinal peptide (VIP) is a neuropeptide present in the lymphoid microenvironment with a multiplicity of actions. Two sources for VIP have been described in the immune system, the terminals present in central and peripheral lymphoid organs and the immune cells. Although VIP is synthesized by lymphocytes, there is no evidence demonstrating that VIP is released, and which stimuli are able to induce VIP production and secretion. In this study, we demonstrated for the first time, that agents that mediate important immune functions, such as proliferation and antigenic stimulation (Con A, LPS, and anti-TCR antibody), inflammation (LPS, TNFalpha, IL-6 and IL-1beta) or apoptosis (dexamethasone) induce the production and release of VIP to the lymphoid microenvironment. We conclude that VIP is produced and secreted by lymphocytes and propose that during an immune response, the timely release of VIP within the lymphoid organs and peritoneum should influence the differentiation and/or downregulation of the ongoing response.     

A molecular basis for interactions between the immune and neuroendocrine systems

Homeostatic and psychologic alterations associated with infections and tumors are very interesting yet poorly understood pathophysiologic responses. Numerous anecdotal and indirect examples suggest that these responses occur through a link between the central nervous and immune systems (for review see Blalock, Bost, & Smith, 1985; Spector & Korneva, 1981; Maestroni & Pierpaoli, 1981; Felton et al., 1985; Jankovic, 1985). Interactions between the two systems are just now being described. One possible mechanism is direct modulation of the immune system by the sympathetic nervous system. This could occur in innervated immune organs such as spleen, thymus, and bone marrow (Felton et al., 1985). The evidence for this is that sympathectomy and lesioning of specific regions of the brain can be shown to both enhance and/or suppress immune responses (Miles et al., 1985; Roszman et al., 1985). Also, the firing rate of hypothalamic neurons is altered during an immune response (Besedovsky et al., 1977). Alternatively, hormonal involvement in immune reactions has been known for some time, in particular the immunosuppressive effects of glucocorticoids (for review see Cupps & Fauci, 1982). Recently, we and others found that neuroendocrine peptide hormones will modulate T and B lymphocytes plus other immunocyte responses (Besedovsky et al., 1977; Cupps & Fauci, 1982; Johnson et al., 1982; Wybran et al., 1979; Hazum, Chang & Cuatrecasas, 1979; O'Dorisio et al., 1981; Gilman et al., 1982; McCain et al., 1982; Mathews et al., 1983; Plotnikoff et al., 1985; Johnson et al., 1984). Furthermore, lymphocytes themselves can synthesize biologically active neuroendocrine hormones (Blalock & Smith, 1980; O'Dorisio et al., 1980; Smith & Blalock, 1981; Smith et al., 1983; Lolait et al., 1984; Ruff & Pert, 1984), as well as possess specific hormone receptors (Blalock et al., 1985; Johnson et al., 1982; Wybran et al., 1979; Hazum et al., 1979; O'Dorisio et al., 1981; Lopker et al., 1980; Payan, Brewster & Goetzl, 1984; Pert et al., 1985). Immune responses (Besedovsky, del Rey & Sorkin, 1981), thymic hormones (Healy et al., 1983), and lymphokines (Lotze et al., 1985; Woloski et al., 1985) have all been shown to exert hormonal effects. Thus, another method for communication between the immune and neuroendocrine systems seems to be through soluble factors such as neuroendocrine hormones. This review will concentrate on the latter topic, in particular on work this laboratory has done over the past few years to show the lymphocyte production and immunoregulatory actions of neuroendocrine hormones.     

The influence of sex hormones on cytokines in multiple sclerosis and experimental autoimmune encephalomyelitis: a review

The female predominance of multiple sclerosis (MS) has suggested that hormonal differences between the sexes must confer some protective effect on males or enhance the susceptibility of females to this disease. There has been evidence that gonadal hormones can modulate the immune response regulated by antigen presenting cells and T cells. These cells control the immune response by the production of interacting pro- and anti-inflammatory cytokines. The first include the acute phase pro-inflammatory cytokines of the innate immune response as well as the T-helper 1 (Th1) cytokines, while the later contain the Th2 cytokines as well as the suppressor cytokines. There is some evidence that MS and experimental autoimmune encephalitis (EAE) are Th1 cell-mediated diseases. For this reason many studies have been done to influence the pro-inflammatory cytokine production of these Th1 cells in favour of an anti-inflammatory immune response as mediated by Th2 cells. However the role of the regulatory T cells in this context is not clearly understood. Here we review the studies concerning the role of sex hormones on the cytokine production in relation to the disease course of MS and EAE and in particular in the light of the recent revival of the regulatory T cells and their suppressive cytokines.     

Sleep and circadian rhythm regulate circulating complement factors and immunoregulatory properties of C5a

The sleep-wake cycle is characterized by complex interactions among the central nervous, the endocrine and the immune systems. Continuous 24-h wakefulness prevents sleep-associated hormone regulation resulting in impaired pro-inflammatory cytokine production. Importantly, cytokines and hormones also modulate the complement system, which in turn regulates several adaptive immune responses. However, it is unknown whether sleep affects the activation and the immunoregulatory properties of the complement system. Here, we determined whether the 24-h sleep-wake cycle has an impact on: (i) the levels of circulating complement factors; and (ii) TLR4-mediated IL-12 production from human IFN-γ primed monocytes in the presence or absence of C5a receptor signaling. For this purpose, we analyzed the blood and blood-derived monocytes of 13 healthy donors during a regular sleep-wake cycle in comparison to 24 h of continuous wakefulness. We found decreased plasma levels of C3 and C4 during nighttime hours that were not affected by sleep. In contrast, sleep was associated with increased complement activation as reflected by elevated C3a plasma levels during nighttime sleep. Sleep deprivation prevented such activation. At the cellular level, C5a negatively regulated TLR4-mediated IL-12p40 and p70 production from human monocytes. Importantly, this regulatory effect of C5a on IL-12p70 production was effective only during daytime hours. Thus, similar to hormones, some complement factors and immunoregulatory properties of C5a are influenced by sleep and the circadian rhythm. Our findings that continuous wakefulness has a negative impact on complement activation may provide a rationale for the immunosupportive functions of sleep.     

Centrally mediated effects of neurohypophyseal hormones

The neurohypophyseal hormones oxytocin and vasopressin cause a variety of biological effects in animals which are mediated by central nervous system mechanisms. Among the best studied of these effects is the modulation of both memory processes and the development of drug tolerance and dependence. Neurohypophyseal hormones have also been shown to alter various physiological parameters such as heart rate and body temperature following central administration. In addition, these peptides can profoundly alter spontaneous, unlearned behavior in several rodent species. Many of the centrally mediated effects of neurohypophyseal hormones have been shown to be elicited at sites within the brain stem and the limbic system where vasopressin and oxytocin occur in cell bodies, axons and nerve terminals, suggesting a physiological role for these peptide effects. The various central effects of neurohypophyseal hormones involve different mechanisms which can be distinguished from one another on the basis of required dose, time-course of action, and structure-activity relationships. Thus, alterations of spontaneous behavior are mediated by putative receptors closely related to vasopressin receptors in blood vessels responsible for the peripheral pressor response while the effects on memory processes are mediated by a mechanism which is not closely related to those involved in the peripheral hormonal effects of the peptides. The influence of neurohypophyseal hormones on memory and attention may be useful clinically. A potential role for these peptides in mental disorders is discussed.     

How cytokines can influence the brain: a role for chemokines?

Following inflammation or infection, cytokines are released in the blood. Besides their effect on the immune system, cytokines can also act in the brain to modulate our behaviors, inducing for example anorexia when produced in large amount. This review focuses on our current knowledge on how cytokines can influence the brain and the behaviors through several possible pathways: modulating peripheral neurons which project to the brain through the vagus nerve, modulating the levels of hormones such as leptin which can act to the brain through the humoral pathway and possibly acting directly in the brain, through the local production of cytokines and chemokines such as SDF-1alpha/CXCL12.     

Bombyx orcokinins are brain-gut peptides involved in the neuronal regulation of ecdysteroidogenesis

Biosynthesis of ecdysteroids, the insect steroid hormones controlling gene expression during molting and metamorphosis, takes place primarily in the prothoracic gland (PG). The activity of the PG is regulated by various neuropeptides. In the silkworm Bombyx mori, these neuropeptides utilize both hormonal and neuronal pathways to regulate the activity of the PG, making the insect an excellent model system to investigate the complex signaling network controlling ecdysteroid biosynthesis. Here we report another group of neuropeptides, orcokinins, as neuronal prothoracicotropic factors. Using direct mass spectrometric profiling of the axons associated with the PG, we detected several peptide peaks which correspond to orcokinin gene products in addition to the previously described Bommo-FMRFamides (BRFas). In situ hybridization and immunohistochemistry revealed that orcokinins are produced in the prominent neurosecretory cells in the ventral ganglia, as well as in numerous small neurons throughout the central nervous system and in midgut endocrine cells. One of the two pairs of BRFa-expressing neurosecretory cells in the prothoracic ganglion coexpresses orcokinin, and these neurons project axons through the transverse nerve and terminate on the surface of the PG. Using an in vitro PG bioassay, we show that orcokinins have a clear prothoracicotropic activity and are able to cancel the static effect of BRFas on ecdysteroid biosynthesis, whereas the suppressive effect of BRFas on cAMP production remained unchanged in the presence of orcokinins. The discovery of a second regulator of PG activity in these neurons further illustrates the potential importance of the PG innervation in the regulation of insect development.     

Neutrophil-activating peptide-1/interleukin-8 mRNA is localized in rat hypothalamus and hippocampus.

Neutrophil-activating peptide-1/interleukin-8 (NAP-1/IL-8) is a cytokine synthesized by various cell types. In the immune system NAP-1/IL-8 is part of an immune cascade initiated by IL-1 production. NAP-1/IL-8 affects hypothalamic function and its production is suppressed by steroids. Therefore, it might be expected that NAP-1/IL-8 would be produced in brain areas involved in the control of the hypothalamic-pituitary-adrenocortical axis (HPA). NAP-1/IL-8 mRNA was localized by in situ hybridization in the paraventricular nucleus of the hypothalamus and hippocampus. Those areas also express the genes encoding interleukin-1-alpha (IL-1 alpha), IL-1 beta, IL-1 receptors, and IL-1 receptor antagonist (IL-1ra). This suggests that an immune cascade, which is well characterized in the immune system, may exist in brain, in areas of relevance to the regulation of stress-related neuroendocrine function.     

Protein hormones and immunity

A number of observations and discoveries over the past 20 years support the concept of important physiological interactions between the endocrine and immune systems. The best known pathway for transmission of information from the immune system to the neuroendocrine system is humoral in the form of cytokines, although neural transmission via the afferent vagus is well documented also. In the other direction, efferent signals from the nervous system to the immune system are conveyed by both the neuroendocrine and autonomic nervous systems. Communication is possible because the nervous and immune systems share a common biochemical language involving shared ligands and receptors, including neurotransmitters, neuropeptides, growth factors, neuroendocrine hormones and cytokines. This means that the brain functions as an immune-regulating organ participating in immune responses. A great deal of evidence has accumulated and confirmed that hormones secreted by the neuroendocrine system play an important role in communication and regulation of the cells of the immune system. Among protein hormones, this has been most clearly documented for prolactin (PRL), growth hormone (GH), and insulin-like growth factor-1 (IGF-I), but significant influences on immunity by thyroid-stimulating hormone (TSH) have also been demonstrated. Here we review evidence obtained during the past 20 years to clearly demonstrate that neuroendocrine protein hormones influence immunity and that immune processes affect the neuroendocrine system. New findings highlight a previously undiscovered route of communication between the immune and endocrine systems that is now known to occur at the cellular level. This communication system is activated when inflammatory processes induced by proinflammatory cytokines antagonize the function of a variety of hormones, which then causes endocrine resistance in both the periphery and brain. Homeostasis during inflammation is achieved by a balance between cytokines and endocrine hormones.     

Immunoglobulin G(1) immune complex upregulates interferon-γ-induced nitric oxide production via ERK1/2 activation in murine microglia

Intrathecal Immunoglobulin G (IgG) is elevated in some central nervous system (CNS) diseases and microglia upregulate Fcγ receptors in various neurological disorders. However, the interaction between IgG or IgG immune complexes and microglial Fcγ receptors is not fully understood. In this study, the effect of IgG(1) immune complexes on microglia was investigated. IgG(1) immune complexes increased nitric oxide production in murine microglia in the presence of interferon (IFN)-γ. These effects were dependent upon IgG(1) immune complex-induced activation of spleen tyrosine kinase with subsequent activation of extracellular signal regulated kinase1/2. Collectively, these results indicate that IgG(1) immune complexes can exert immunomodulatory effects in various central nervous system disorders.     

The emotional ear in stress

Stress of some kind is encountered everyday and release of stress hormones is essential for adaptation to change. Stress can be physical (pain, noise exposure, etc.), psychological (apprehension to impending events, acoustic conditioning, etc.) or due to homeostatic disturbance (hunger, blood pressure, inner ear pressure, etc.). Persistent elevated levels of stress hormones can lead to disease states. The aim of the present review is to bring together data describing morphological or functional evidence for hormones of stress within the inner ear. The present review describes possible multiple interactions between the sympathetic and the complex feed-back neuroendocrine systems which interact with the immune system and so could contribute to various inner ear dysfunctions such as tinnitus, vertigo, hearing losses. Since there is a rapidly expanding list of genes specifically expressed within the inner ear this clearly allows for possible genomic and non-genomic local action of steroid hormones. Since stress can be encountered at any time throughout the life-time, the effects might be manifested starting from in-utero. These are avenues of research which remain relatively unexplored which merit further consideration. Progress in this domain could lead towards integration of stress concept into the overall clinical management of various inner ear pathologies.     

Immunological Treatments for Autism

Several investigators, including ourselves, have reported significant changes in various immune responses in children with autism. These changes demonstrate dysregulation of the immune system (deficiency in some components of the immune system and excesses in others). In addition, certain genes in the major histocompatibility complex (that regulates immune responses) appear to be involved in autism. Based upon immunological abnormalities, various treatment modalities have been applied to children with autism. In this brief review, these immunological changes and various biological therapies are analyzed and summarized.     

The importance of being receptive

Neuroendocrine system and immune system can communicate via the use of soluble mediators like hormones, neurotransmitters and cytokines. The level of mediators secreted by either of these systems creates the milieu in which immune and neuroendocrine responses take place. For adequate communication between the systems, receptors for hormones, neurotransmitters and cytokines are required. This review describes the role of regulated expression and function of receptors for hormones and neurotransmitters within the immune system in neuroendocrine-immune communication.