Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being

The neuroendocrine system affects the immune system through the neuroendocrine humoral outflow via the pituitary, and through direct neuronal influences via the sympathetic, parasympathetic (cholinergic) and peptidergic/sensory innervation of peripheral tissues. Circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune functions, such as antigen presentation, antibody production, lymphocyte activity, proliferation and traffic, and the secretion of cytokines including the selection of T helper (Th)1 or Th2 cytokine responses. During inflammation, the activation of the stress system, through induction of a Th2 shift protects the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones, substance P, ATP and the activation of the corticotropin-releasing hormone/substance P-histamine axis may actually facilitate inflammation, through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor (TNF)-alpha and CRP production. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression and atherosclerosis. Better understanding of the neuroendocrine control of inflammation may provide critical insights into mechanisms underlying a variety of common human immune-related diseases.     

Hormones,Lymphohemopoietic Cytokines and the Neuroimmune Axis

The classical distinction between hormones and cytokines has become increasingly obscure with the realization that homeostatic responses to infection involve coordinated changes in both the neuroendocrine and immune systems. The hypothesis that these systems communicate with one another is supported by the ever-accruing demonstrations of a shared molecular network of ligands and receptors. For instance, leukocytes express receptors for hormones and these receptors modulate diverse biological activities such as the growth, differentiation and effector functions. Leukocyte lineages also synthesize and secrete hormones, such as insulin-like growth factor-I (IGF-I), in response to both growth hormone (GH) and also to cytokines such as tumor necrosis factor-α (TNF-α). Since hormones share intracellular signaling substrates and biological activities with classical lymphohemopoietic cytokines, neuroendocrine and immune tissues share a common molecular language. The physiological significance of this shared molecular framework is that these homeostatic systems can intercommunicate. One important example of this interaction is the mechanism by which bacterial lipopolysaccharide, by eliciting a pro-inflammatory cytokine cascade from activated leukocytes, modulate pituitary GH secretion as well as other CNS-controlled behavioral and metabolic events. This article reviews the cellular and molecular basis for this communication system and proposes novel mechanisms by which neuroendocrine-immune interactions converge to modulate disease resistance, metabolism and growth.     

Interactions between age and the neuroendocrine and immune systems.

Three conclusions are suggested by some of the recent work on aging, immunology and the neuroendocrine system. 1) There appears to be sufficient data to implicate the neuroendocrine system in both the maturation and the senescence of at least some components of the immune system. 2) The thymus by its presence or its absence appears to influence certain functions of the pituitary; thus, there appears to be a possible reciprocal relationship between the pituitary and the thymus. 3) Changes in the levels of pituitary hormones or hormones that are controlled by the pituitary can restore in older rats and mice certain functions that are generally considered as part of the immune surveillance and defense system. Consequently, it can be hoped that further studies of neuroendocrine-immune relationships might lead to an understanding of some of the causes for the decline in immune competence with age in mammals.     

Cross-regulation in development of neuroendocrine and immune systems

Cross-regulatory effects of immune and neuroendocrine systems on their appearance and functioning occur during a whole life period. At different stages of ontogenesis, the functions of these systems are diverse. In perinatal ontogenesis hormones, neuropeptides and neurotransmitters control the processes of growth and differentiation of various embryo tissues, particularly lymphoid. In the postnatal period, their functions are mostly in homeostasis maintaining of the immune system in response to changes of the environment. Conversely, transmitters of the immune system, such as cytokines, whose synthesis is increased in inflammation, and thymic peptides, program the development of the neuroendocrine system of the embryo. The perinatal period is crucial for final appearance of these systems. Changes in one of the interacting systems, caused by negative environmental factors at this stage, usually provoke changes in other developing systems for a long period. Plasticity of physiological systems in perinatal development allows the organism to adapt to changed conditions. However, these changes can limit physiological functions in interacting systems and induce the appearance of various pathologies in postnatal life.     

Cross-talk among immune and neuroendocrine systems in molluscs and other invertebrate models

The comparison between immune and neuroendocrine systems in vertebrates and invertebrates suggest an ancient origin and a high degree of conservation for the mechanisms underlying the integration between immune and stress responses. This suggests that in both vertebrates and invertebrates the stress response involves the integrated network of soluble mediators (e.g., neurotransmitters, hormones and cytokines) and cell functions (e.g., chemotaxis and phagocytosis), that interact with a common objective, i.e., the maintenance of body homeostasis. During evolution, several changes observed in the stress response of more complex taxa could be the result of new roles of ancestral molecules, such as ancient immune mediators may have been recruited as neurotransmitters and hormones, or vice versa. We review older and recent evidence suggesting that immune and neuro-endocrine functions during the stress response were deeply intertwined already at the dawn of multicellular organisms. These observations found relevant reflections in the demonstration that immune cells can transdifferentiate in olfactory neurons in crayfish and the recently re-proposed neural transdifferentiation in humans.     

Neural immune pathways and their connection to inflammatory diseases

Inflammation and inflammatory responses are modulated by a bidirectional communication between the neuroendocrine and immune system. Many lines of research have established the numerous routes by which the immune system and the central nervous system (CNS) communicate. The CNS signals the immune system through hormonal pathways, including the hypothalamic-pituitary-adrenal axis and the hormones of the neuroendocrine stress response, and through neuronal pathways, including the autonomic nervous system. The hypothalamic-pituitary-gonadal axis and sex hormones also have an important immunoregulatory role. The immune system signals the CNS through immune mediators and cytokines that can cross the blood-brain barrier, or signal indirectly through the vagus nerve or second messengers. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. This review discusses neuroimmune interactions and evidence for the role of such neural immune regulation of inflammation, rather than a discussion of the individual inflammatory mediators, in rheumatoid arthritis.     

Neuroendocrine-immune (NEI) circuitry from neuron-glial interactions to function: Focus on gender and HPA-HPG interactions on early programming of the NEI system

Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life. Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function. Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity. The neuroendocrine-immune system is very sensitive to preperinatal experiences, including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities. We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level. In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators. Hence, neuron-glial signalling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers. The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized. The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.     

Thymectomy-induced deterioration of learning and memory.

Age-associated immunodeficiency and cognitive deterioration are two predominant features of the aging process, but the mutual influences between them are not clear yet. Research on the neuroendocrine immunomodulation (NIM) network indicate reciprocal interactions between the neuroendocrine and the immune systems mediated by neurotransmitters, neuropeptides, hormones and cytokines, which form an integrated network to maintain normal physiological functions of the body. An imbalance in the NIM network is believed to accelerate the aging process, in which the thymus plays an important role. We recently discovered that thymectomy in mice not only reduces the immune response, but also deteriorates learning performances. Cytokines such as interleukin-1, interleukin-6 and tumor necrosis factor, and corticosterone affect the induction of hippocampal long-term potentiation, a synaptic model of memory. Clinical studies have demonstrated that Alzheimer's patients show disordered immune function in addition to cognitive deficit, and the brain lesions of Alzheimer's patients may be associated with abnormal immune reactions occurring in the brain. With these findings, it is speculated that the disordered immune function may induce an imbalance in the NIM network, which consequently influences central cognitive function.     

Relationships between the brain and the immune system

The concept that the brain can modulate activity the immune system stems from the theory of stress. Recent advances in the study of the inter-relationships between the central nervous system and the immune system have demonstrated a vast network of communication pathways between the two systems. Lymphoid organs are innervated by branches of the autonomic nervous system. Accessory immune cells and lymphocytes have membrane receptors for most neurotransmitters and neuropeptides. These receptors are functional, and their activation leads to changes in immune functions, including cell proliferation, chimiotactism and specific immune responses. Brain lesions and stressors can induce a number of changes in the functioning of the immune system. All these changes are not necessarily mediated by the neuroendocrine system. They can also be dependent on autonomic nerve function. The communication pathways that link the brain to the immune system are normally activated by signals from the immune system, and they serve to regulate immune responses. These signals originate from accessory immune cells such as monocytes and macrophages and they are represented mainly by proinflammatory cytokines. Proinflammatory cytokines produced at the periphery act on the brain via two major pathways: (1) a humoral pathway allowing pathogen specific molecular patterns to act on Toll-like receptors in those brain areas that are devoid of a functional blood-brain barrier, the so-called circumventricular areas; (2) a neural pathway, represented by the afferent nerves that innervate the bodily site of infection and injury. In both cases, peripherally produced cytokines induce the expression of brain cytokines that are produced by resident macrophages and microglial cells. These locally produced cytokines diffuse throughout the brain parenchyma to act on target brain areas so as to organise the central components of the host response to infection (fever, neuroendocrine activation, and sickness behavior).     

Neuroendocrine-immune circuits,phenotypes, and interactions

Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions.     

Interactions between the immune and neuroendocrine systems: clinical implications

The endocrine and immune systems are interrelated via a bidirectional network in which hormones affect immune function and, in turn, immune responses are reflected in neuroendocrine changes. This bidirectional communication is possible because both systems share a common "chemical language" that results from a sharing of common ligands (hormones and cytokines) and their specific receptors. Cytokines are important partners in this crosstalk. They play a role in modulating the hypothalamo-pituitary-adrenal (HPA) axis responses at all three levels: the hypothalamus, the pituitary gland and the adrenals. Acute effects of cytokines are produced at the central nervous system level, particularly the hypothalamus, whereas pituitary and adrenal actions are slower and are probably involved during prolonged exposure to cytokines such as during chronic inflammation or infection. Several mechanisms have been proposed by which peripheral cytokines may gain access to the brain. They include an active transport through the blood-brain barrier, a passage at the circumventricular organ level, as well as a neuronal pathway through the vagal nerve. The immune-neuroendocrine interactions are involved in numerous physiological and pathophysiological conditions and the interactions with the HPA axis may represent a mechanism through which the immune system, by stimulating the production of glucocorticoids, avoids an overshoot of inflammatory response. They may also be involved in the state of hypogonadism, of hypothyroidism and growth inhibition which can occur during inflammatory and infectious diseases. The crosstalk between the immune and endocrine systems is important to homeostasis, since the interactions can produce various appropriate adaptative responses when homeostasis is threatened.     

Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinology

During the past decade, the immune and endocrine systems have been discovered to interact in controlling physiologic processes as diverse as cell growth and differentiation, metabolism, and even human and animal behavior. The interaction between these two major physiological systems is a bi-directional process. While it has been well documented that hormones, including prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid-stimulating hormone (TSH), regulate a variety of immune events, a great deal of data have accumulated supporting the notion that cytokines from the innate immune system also affect the neuroendocrine system. Communication between these two systems coordinates processes that are necessary to maintain homeostasis. Proinflammatory cytokines often act as negative regulatory signals that temper the action of hormones and growth factors. This system of 'checks and balances' is an active, ongoing process, even in healthy individuals. Dysregulation of this process has been implicated as a potential pathogenic factor in the development of co-morbid conditions associated with several chronic inflammatory diseases, including type 2 diabetes, cardiovascular disease, cerebrovascular disease, inflammatory bowel disease, rheumatoid arthritis, major depression, and even normal aging. Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I). We also highlight that IGF-I can induce resistance or reduce sensitivity to brain TNFalpha and discuss how TNFalpha, IL-1beta, and IGF-I interact to regulate several aspects of behavior and cognition.     

Neuroendocrine control of reproduction in Crustacea

The neuroendocrine factors synthetized by various regions of the nervous system and which have inhibiting or stimulating effects can control the male and female physiology of malacostraca via sexual hormones and moulting hormone. There are between decapods and peracarids functional homologies but some differences can be noticed as to the localization of these antagonistic neurosecretory systems. The functioning of these systems is regulated by external factors such as the photoperiod and the temperature. The interactions between these different neurohormones, the sexual hormones and the moulting hormone are discussed.     

From the neuroendocrinology of lymphocytes toward a molecular basis of the network theory

The cells of the immune system produce and respond to hormones that were once thought to be restricted to the neuroendocrine system. By applying a novel methodology based on the molecular recognition hypothesis, the isolation and purification of receptors shared between the immune and neuroendocrine systems was accomplished. Biochemical analysis revealed them to be virtually identical with respect to their physicochemical and functional properties. Thus, bidirectional communication between the immune and neuroendocrine systems seems to result from a common set of hormones and receptors which are shared by the two systems. Furthermore, the molecular recognition hypothesis has revealed that homologues of the binding sites of these same hormone receptor pairs may be contained within the hypervariable regions of immunoglobulins and therefore constitute part of the immunologic network.     

Hypothalamic releasing hormones mediating the effects of interleukin-1 on sleep

There is a substantial literature describing the interactions between the endocrine and immune systems. Although such interactions are less well known within the brain, one major brain function altered during inflammation and infection and by several endocrine hormones is sleep. Pathological disturbances, be they inflammation, infectious disease, and/or sleep deprivation, result in altered hypothalamus-pituitary function and cytokine metabolism. In respect to hormone secretion from the pituitary, cytokines are now recognized to play an important role in modulating the neuroendocrine system. Changes in sleep provide a useful illustration of the interactions between cytokines and the hypothalamus-pituitary axis. Evidence linking interleukin-1 (IL-1) to growth hormone releasing hormone and to corticotropin releasing hormone in regard to their effects on sleep is reviewed.     

Integrated communication between the nervous, endocrine and immune systems

Several data accumulated over recent years on the mechanisms underlying the interactions between the brain, hormones and the immune system. These data concern two major avenues of research: the evidence that brain-controlled, behavioral parameters can modulate the response of immunocompetent cells, and an increasing awareness that a number of chemical signals - neurotransmitters, hormones or mediators of immunity - are not, as previously believed, specific of given sets of tissues or of functions, but that, on the contrary, they can be produced and recognized by cellular elements belonging to any of those three systems. There is indeed evidence to indicate that signaling molecules involved in cellular communication are 'banalized': that means that their receptors are liable to be expressed in almost any tissue by a wide variety of cells. This statement, together with the discovery that intercellular regulation is multifactorial - that is, depends at any given time upon messages built up by combinations of signal molecules rather than by isolated transmitters - raises a certain number of theoretical problems as to the manner by which cells extract messages out of an important background noise. In the present paper, some of those theoretical problems will be presented in a summarized form, and their relevance for the interpretation of neuroendocrine or neuroimmunological interactions will be discussed.     

The myotropic peptides of Locusta migratoria: Structures, distribution, functions and receptors

The search for myotropic peptide molecules in the brain, corpora cardiaca, corpora allata suboesophageal ganglion complex of Locusta migratoria using a heterologous bioassay (the isolated hindgut of the cockroach, Leucophaea maderae) has been very rewarding. It has lead to the discovery of 21 novel biologically active neuropeptides. Six of the identified Locusta peptides show sequence homologies to vertebrate neuropeptides, such as gastrin/cholecystokinin and tachykinins. Some peptides, especially the ones belonging to the FXPRL amide family display pleiotropic effects. Many more myotropic peptides remain to be isolated and sequenced. Locusta migratoria has G-protein coupled receptors, which show homology to known mammalian receptors for amine and peptide neurotransmitters and/or hormones. Myotropic peptides are a diverse and widely distributed group of regulatory molecules in the animal kingdom. They are found in neuroendocrine systems of all animal groups investigated and can be recognized as important neurotransmitters and neuromodulators in the animal nervous system. Insects seem to make use of a large variety of peptides as neurotransmitters/neuromodulators in the central nervous system, in addition to the aminergic neurotransmitters. Furthermore quite a few of the myotropic peptides seem to have a function in peripheral neuromuscular synapses. the era in which insects were considered to be “lower animals” with a simple neuroendocrine system is definitely over. Neural tissues of insects contain a large number of biologically active peptides and these peptides may provide the specificity and complexity of intercellular communications in the nervous system.     

Bellini, Carpaccio, and receptors in the central nervous system.

With the convergence of science from the fields of neurobiology and immunology, many exciting and challenging surprises have emerged regarding cytokines, neuroendocrine hormones, neuropeptides, excitatory amino acids, and their receptors. For some time neurobiologists have known that subsets of neural cells had different receptors for the same ligand. Those subsets of cells could be as different as neurons and astrocytes and as closely related as astrocytes from different lineages or anatomical areas. The neurobiological puzzle has been to determine the functional meaning of these differences. Immunologists in contrast have long understood the clear cut differences between T and B lymphocytes or T helper/inducer and T cytotoxic/suppressor cells and their response to cytokines. However, it is only very recently that they have discovered preferential use by these cells of different receptors for an identical cytokine ligand. Indeed, identical cytokines in the central nervous system and immune response may induce their pleiotropic responses by utilizing different receptors in these two systems. Immunologic paradigms may help neurobiologists predict the existence of subsets of neural cells and their function. Likewise, neurobiology may enable immunologists to predict roles for receptors in gene families as well as the existence of as yet unidentified receptors.     

Neurochemistry of Brain Neuroendocrine Immune System: Signal Molecules

The aim of this review is not so much to show the problem of neuroendocrine, neurophysiologic, and neurochemical mechanisms of the immune system regulation of the organism by brain (there is a great deal of literature about it), as to solve the problem of whether the brain itself is an immune organ, and also to define cellular, neurochemical, and immunological properties of the brain for its immune defense when the blood-brain barrier is not damaged in spite of the penetration of the infection to brain. The accumulated literary data on CNS interaction with the immune system, expression of several cytokines and their receptors in the neurons of human brain culture, in astrocytes and microglia, all testify to the existence of a brain immune system. Recently studies appeared on the expression of major histocompatibility complex in brain neurons. It does not exclude the possibility of expression of immunoglobulins (or immunoglobulin-like proteins) in brain cells. Data obtained by us on the biosynthesis of a number of known interleukins and new cytokines in neurosecretory neurons of hypothalamus (N.Paraventricularis and N. Supraopticus) demonstrate that neuroendocrine nuclei of the hypothalamus are the center for neuroendocrine and immune systems of brain.