Special feature for the Olympics: effects of exercise on the immune system: neuropeptides and their interaction with exercise and immune function

It is known today that the immune system is influenced by various types of psychological and physiological stressors, including physical activity. It is well known that physical activity can influence neuropeptide levels both in the central nervous system as well as in peripheral blood. The reported changes of immune function in response to exercise have been suggested to be partly regulated by the activation of different neuropeptides and the identification of receptors for neuropeptides and steroid hormones on cells of the immune system has created a new dimension in this endocrine-immune interaction. It has also been shown that immune cells are capable of producing neuropeptides, creating a bidirectional link between the nervous and immune systems. The most common neuropeptides mentioned in this context are the endogenous opioids. The activation of endogenous opioid peptides in response to physical exercise is well known in the literature, as well as the immunomodulation mediated by opioid peptides. The role of endogenous opioids in the exercise-induced modulation of immune function is less clear. The present paper will also discuss the role of other neuroendocrine factors, such as substance P, neuropeptide Y and vasoactive intestinal peptide, and pituitary hormones, including growth hormone, prolactin and adrenocorticotrophin, in exercise and their possible effects on immune function.     

免疫细胞内源性儿茶酚胺的免疫调节作用

机体内儿茶酚胺（catecholamines,CAs）包括去甲肾上腺素（norepinephrine,NE）、肾上腺素（epinephrine,E）和多巴胺（dopamine,DA）。CAs由神经元和内分泌细胞合成和分泌,其主要功能是调节心血管、呼吸和消化等内脏活动。近三十年来的研究说明,CAs也参与调控机体的免疫功能,但CAs的这种免疫调节作用一般视为神经和内分泌系统调节的介导作用。然而,近年来的研究发现,免疫细胞也能合成CAs,这是对传统观念的一种补充和提高。免疫细胞内存在经典的CAs代谢途径,既有合成CAs的酪氨酸羟化酶（tyrosine hydroxylase,TH）又有降解CAs的单胺氧化酶（monoamine oxidase,MAO）和儿茶酚氧位甲基移位酶（catechol-O-methyl transferase,COMT）。免疫细胞合成的内源性CAs可以调控细胞的增殖、分化、凋亡和细胞因子生成等多种免疫功能。CAs的这些作用可能主要通过自分泌或旁分泌途径作用于免疫细胞上相应受体和细胞内环磷酸腺苷（cyclicAMP,cAMP）实现。细胞内氧化应激机制可能也参与免疫细胞内源性CAs的免疫调节作用。此外,一些自身免疫性疾病如多发性硬化、风湿性关节炎可能也与免疫细胞内CAs的代谢异常有关。上述发现不仅为免疫系统有可能成为除神经和内分泌系统以外的第三个CA能系统提供了证据,而且为免疫系统内源性CAs的功能意义拓展了认识。     

Nonopiate active proenkephalin-derived peptides are secreted by T helper cells

Recent investigations have shown that the neuroendocrine and immune systems profoundly affect each other. In part, these interactions occur via common chemical messengers and receptors. One possible shared chemical messenger is the opioid precursor preproenkephalin, for which high concentrations of messenger RNA are present in brain, adrenal, and activated T helper cells. Because the biologic action of most peptide messengers depends on the posttranslational processing of the precursor, we have examined T helper cell lines for the production of proenkephalin-derived peptides. These peptides were characterized by multiple radioimmunoassays, gel filtration chromatography, and opiate radioreceptor assays. We found that activated T helper cells secrete significant concentrations of high-molecular-weight, opiate-inactive peptides, which are distinct from the proenkephalin-derived peptides of the neuroendocrine system. These studies clearly indicate cell-specific processing of proenkephalin, and suggest that the T helper cell-secreted products may have nonopiate receptor-mediated actions.     

The role of endogenous opioids and their receptors in the immune system.

Opioid peptides appear to be dynamic signaling molecules that are produced within the immune system and are active regulators of an immune response. Furthermore, the receptors for these peptides occurring on immunocyte membranes share characteristics with neuronal opioid receptors, including molecular size, immunogenicity, and the use of specific intracellular signaling pathways. Recent studies of the interaction of opioids with cytokines have indicated that opioid peptides are intimately involved within the immune system. Specifically, opioids, including 2-n-pentyloxy-2-phenyl-4-methyl-morpholine, naloxone, and beta-endorphin, have been shown to interact with IL-2 receptors (134) and regulate production of IL-1 and IL-2 (48-50, 135). Conversely, IL-1 has been shown to up-regulate opioid peptide binding in brain tissue (136). Furthermore, the induction of IL-1 by opioids has also been identified in the invertebrate Mytilus, indicating the evolutionary conservation of this relationship (137). These results seem to typify the intricate association between the immune and neuroendocrine systems through opioid pathways. It is predicted that future endeavors will use this relationship to diagnose and treat specific diseases that have at their basis neuroendocrine and immunologic imbalances.     

Immune mechanisms in pain control

Pain inhibition can be induced by immune‐derived opioids interacting with opioid receptors on peripheral sensory nerves. These receptors are up‐regulated in inflammation (1). Opioid peptides are synthesised in circulating immune cells which migrate to injured tissue. This is orchestrated by selectins and other adhesion molecules located on immunocytes and on vascular endothelium (2). In response to releasing stimuli the opioids are secreted, activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. These effects occur in the periphery and are devoid of central side‐effects such as respiratory depression, sedation, dysphoria or dependence. Targeting of immune cells containing opioids to injured tissues is a novel concept of pain control and opens potential new therapeutic approaches.     

Opioids in neuropathic pain

Pain inhibition can be induced by immune-derived opioids interacting with opioid receptors on peripheral sensory nerves. These receptors are up-regulated in inflammation (1). Opioid peptides are synthesised in circulating immune cells which migrate to injured tissue. This is orchestrated by selectins and other adhesion molecules located on immunocytes and on vascular endothelium (2). In response to releasing stimuli the opioids are secreted, activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. These effects occur in the periphery and are devoid of central side-effects such as respiratory depression, sedation, dysphoria or dependence. Targeting of immune cells containing opioids to injured tissues is a novel concept of pain control and opens potential new therapeutic approaches.     

The next frontier in the molecular biology of the opioid system

The analgesic and euphoric properties of some plant alkaloids such as morphine have been known and exploited for centuries. In contrast, only during the last twenty years have we begun to unravel the molecular basis by which opiates exert their effects, mechanisms important to our general understanding of the nervous system. The analgesic response to opiates is the result of a cascade of biochemical events that are triggered by the interaction of the opiate with specific macromolecular components found on the membranes of nervous system tissues, the opioid receptors. The endogenous ligands of these receptors are small peptides, the opioid peptides. Although much has been learned about the structures and the mode of synthesis of the opioid peptides, little is understood about the structure of their receptors. The application of molecular genetic techniques was of great importance to the studies of the opioid peptides. It is now expected that this same technology will unravel the physical mysteries of the opioid receptors.     

Endogenous opioid peptides in regulation of innate immunity cell functions

Endogenous opioid peptides comprise a group of bioregulatory factors involved in regulation of functional activity of various physiological systems of an organism. One of most important functions of endogenous opioids is their involvement in the interaction between cells of the nervous and immune systems. Summary data on the effects of opioid peptides on regulation of functions of innate immunity cells are presented.     

Sequence of small cardioactive peptide A: a second member of a class of neuropeptides in Aplysia

Previous studies have shown that the nervous system and other tissues of molluscs contain a number of peptides that potently excite molluscan hearts. Two such peptides, termed small cardioactive peptides A and B (SCPA and SCPB) are present in large quantities in the nervous system of Aplysia. These peptides are widely distributed within the CNS and peripheral tissues and have been found to be potent modulators of synaptic transmission in Aplysia. SCPB has previously been purified from nervous tissue and sequenced. In this paper, we report the purification of SCPA and propose its sequence. This sequence was confirmed by comparing the chromatographic properties of native SCPA (labelled in organ culture) with a synthetic peptide that has the proposed sequence. A significant proportion of the sequence of the two SCPs is conserved, indicating that they are members of the same peptide class, a finding that is consistent with the recent observation that the two peptide sequences are present in a single precursor.     

Role of Opioid Peptides in Behavior of Invertebrates

Opioid peptides have been revealed in representatives of practically all large taxonomic groups of invertebrates, and the opiate receptors are found even in unicellulars. The opioid system seems to belong to the evolutionary ancient signal systems. The comparative data indicate that the most conservative and ancient function of opioids is control of the adequate level of protective reactions. In the infusorian Stentor the opiate ligands suppress a contractile response to mechanical stimulation, i.e., the protective behavior. In all studies multicellular invertebrates, agonists also suppress protective behavior, whereas antagonists produce opposite effects. This initially signal meaning of opioids might have become a basis for divergent development of their functions in evolution. Already in higher invertebrates, molluscs and arthropods, many functions of opioids, for example, stress-induced analgesia, regulation of feeding and mating behavior, of social aggression, are similar to those in vertebrates. It is suggested that the main events in formation of functions of the endogenous opioid system have occurred in the lower invertebrates that have remained so far the least studied.     

Association of enkephalin catabolism inhibitors and CCKB antagonists: A potential use in the management of pain and opioid addiction

The overlapping distribution of opioid and cholecystokinin (CCK) peptides and their receptors (μ and δ opioid receptors; CCK-A and CCK-B receptors) in the central nervous system have led to a large number of studies aimed at clarifying the functional relationships between these two neuropeptides. Most of the pharmacological studies devoted to the role of CCK and enkephalins have been focused on the control of pain. Recently the existence of regulatory mechanisms between both systems have been proposed, and the physiological antagonism between CCK and endogenous opioid systems has been definitely demonstrated by coadministration of CCK-B selective antagonists with RB 101, a systemically active inhibitor, which fully protects enkephalins from their degradation. Several studies have also been done to investigate the functional relationships between both systems in development of opioid side-effects and in behavioral responses. This article will review the experimental pharmacology of association of enkephalin-degrading enzyme inhibitors and CCK-B antagonists to demonstrate the interest of these molecules in the management of both pain and opioid addiction. Special issue dedicated to Dr. Eric J. Simon.     

Peptides as regulators of the immune system: emphasis on somatostatin

Study of the communication between nervous and immune systems culminated in the understanding that cytokines, formerly considered exclusively as immune system-derived peptides, are endogenous to the brain and display central actions. More recently, immune cells have been recognized as a peripheral source of “brain-specific” peptides with immunomodulatory actions. This article reviews studies concerning reciprocal effects of selected cytokines and neuropeptides in the nervous and immune systems, respectively. The functional equivalence of these two categories of communicators is discussed with reference to the example of the actions of neuropeptide somatostatin in the immune system.     

Physiological, pathophysiological and pharmacological aspects of exogenous and endogenous opiates

Endogenous opioid peptides have been detected not only in the central nervous system but also in the peripheral autonomic nervous system of the gastrointestinal tract and pancreas and several other organs. In addition opioid active peptides have been found in certain nutrients such as wheat gluten and bovine and human milk. Functional studies have presented evidence for a participation of endogenous opioids in the regulation of certain pituitary and gastrointestinal functions. Apart from being a physiological neuroregulator there is evidence that endogenous opioids might play a role as a pathogenetic factor in various clinical disorders. The evidence for these different aspects of opioid function is reviewed in the present article.     

The role of melanocortins and their receptors in inflammatory processes,nerve regeneration and nociception

The melanocortins are a family of bioactive peptides derived from proopiomelanocortin. Those peptides, included among hormones and comprising ACTH, alpha-MSH, beta-MSH and gamma-MSH, are best known mainly for their physiological effects, such as the control of skin pigmentation by alpha-MSH, and ACTH effects on pigmentation and steroidogenesis. Melanocortins are released in various sites in the central nervous system and in peripheral tissues, and participate in the regulation of multiple physiological functions. They are involved in grooming behavior, food intake and thermoregulation processes, and can also modulate the response of the immune system in inflammatory states. Research of the past decade provided evidence that melanocortins could elicit their diverse biological effects by binding to a distinct family of G protein-coupled receptors with seven transmembrane domains. To date, five melanocortin receptor genes have been cloned and characterized. Those receptors differ in their tissue distribution and in their ability to recognize various melanocortins. These advances have opened up new horizons for exploring the significance of melanocortins, their ligands and their receptors for a variety of important physiological functions. We reviewed the origin of MSH peptides, the function and distribution of melanocortin receptors and their endogenous and exogenous ligands and the role of melanocortins and their receptors in inflammatory processes, nerve regeneration and nociception. Moreover, we analyzed their interaction with opioid peptides and finally, we discussed the postulated role of the melanocortin system in pain transmission at the spinal cord level.     

Mitogenic activation of the human lymphocytes induce the release of proenkephalin derived peptides

Several reports indicate that enkephalins participate in lymphocyte proliferation and several events of the immune response. It has been proposed that peptides involved in these processes may originate in the nervous system or endocrine glands. We have found that human peripheral blood lymphocytes (PBL) activated with a mitogenic agent contain and release proenkephalin derived peptides. The kinetics of met-enkephalin and cryptic products of proenkephalin in PBL activated with phytohemaglutinin (PHA) were studied. Peptides were released to the supernatant of stimulated PBL, reaching the highest values after 18 to 24 hours. The material secreted corresponds to high, intermediate and low molecular weight peptides derived from proenkephalin, displaying met-enkephalin and synenkephalin (proenkephalin 1-70) immunoreactivity. Therefore, an intrinsic lymphocytic proenkephalin system is induced by PHA and may play an important role in the regulation of the immune response.     

A model for exploring afferent signals from the immune system to the nervous system

Mechanisms of information transmission from the immune system to the nervous system have been studied. The results of the studies support the assumption that these signals can be transmitted by oligopeptides (the products of limited proteolysis) which are the fragments found in the active sites of many regulatory peptides of the nervous and immune systems. The testing of a synthesized tripeptide (Ser-Lys-Asp) has shown that it inhibits the antibody-forming cells in intact mice only in response to the administration of large antigen doses and exerts a protective effect against viral infection. When added to the culture of the incubated leukocytes from the peripheral blood of the oncological patients, the tripeptide lowers an increased or normal functional activity of natural killers. In rabbits, tripeptide administration brings about a complex long-lasting reorganization of bioelectrical activity in subcortical structures of the brain.     

Invertebrate and vertebrate neuroimmune and autoimmunoregulatory commonalties involving opioid peptides

1. Evidence for bidirectional interrelationships between the nervous system and immune systems of vertebrates and invertebrates involving opioid peptides is briefly discussed. 2. The involvement of opioid peptides in autoimmunoregulatory communication also is discussed. 3. The presence of mammalian interleukin-like (1 & 6) and tumor necrosis factor-like molecules in invertebrates is reviewed as well as an apparent cascading system for these signal molecules. 4. The significance of ACTH and MSH in cellular immunosuppression and autoimmunoregulation is discussed in the context of a potential role in schistosomiasis and human immunodeficiency virus actions. 5. The review concludes with the hypothesis that the mammalian immune system has its origin in the invertebrate immune/defense system given the many similarities noted in the review based on new knowledge about the more "primitive" system.     

Evidence of opiates and opioid neuropeptides and their immune effects in parasitic invertebrates representing three different phyla: Schistosoma mansoni, Theromyzon tessulatum, Trichinella spiralis

Studies done in our laboratories have demonstrated that the parasitic trematode, Schistosoma mansoni is capable of producing several proopiomelanocortin (POMC) peptides including beta-endorphin, adrenocorticotropin (ACTH), melanocyte stimulating hormone (alphaMSH) and enkephalin as well as morphine. Some of these opioids have been demonstrated to be immunosuppressive and may play an important part in immune evasion by these parasites. The parasitic nematode Trichinella spiralis also produces immune suppressive substances in vitro as well as causes immune suppression in its encysted stage in vivo. We recently have demonstrated the presence of morphine in both infected mice and in the nematode by HPLC and RIA. In a recent study of the leech Theromyzon tessulatum, we demonstrated the presence of proopiomelanocortin (POMC) and its derived peptides, ACTH and alphaMSH, in the immune tissues. The peptide was cloned and extensively purified by HPGPC and reversed-phase HPLC, and then sequenced. The 25.4 kDa protein was purified by gel permeation chromatography, anti-ACTH-affinity column separation followed by reversed-phase HPLC. Its amino acid determination was performed by Edman degradation, enzymatic treatments and electrospray mass spectrometry. The structure of the leech POMC-like precursor and its derived peptides demonstrates considerable amino acid sequence similarity with mammalian POMC. Taken together, these studies demonstrate that opiates and opioid neuropetides are present in invertebrates and their immunoregulatory actions have been conserved during evolution. The role of opiates and opioid peptides in immune and behavior modification of hosts is also discussed.     

Effect of bone marrow opioid peptides on antibody formation in the productive phase of the immune response

The cells of intact spinal cord produce a group of biologically active peptides--myelopeptides (MP) stimulating antibody formation at peak of immune response and exerting an analgesic endorphin-like effect. The experiments on comparative studies of antibody-stimulating effect of synthetic opioid peptides and MP have shown that the mixture of opioid substances composed in aliquots corresponding to their content in MP has an antibody-stimulating effect similar to that of MP. Synthetic beta-endorphin also enhances the antibody formation during the productive phase of immune response at doses 1000-fold lower than its MP level. Leu- and met-enkephalins have no antibody-stimulating effect. An antagonist opiate, naloxone, blocks the antibody-stimulating activity of both opiates and MP. A close correlation between antibody-stimulating and analgetic endorphin-like MP activity has been established.