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.     

Neuroendocrine–immune interactions in homeostasis and autoimmunity

Recent experimental evidence confirms the interrelationships between the central nervous, neuroendocrine and immune systems. Indeed, extensive duality exists in the use of neurotransmitters, hormones and receptors each system displays. In the present annotation, the effect of cytokines, soluble mediators of immune function, on the CNS and neuroendocrine systems is addressed and conversely, we discuss the modification of the immune compartment by the sympathetic nervous and neuroendocrine systems, with particular reference to the role of noradrenaline and corticosterone. Dysfunction between the systems is considered in the context of autoimmune conditions, with emphasis on experimental allergic encephalomyelitis and the contribution of corticosterone–driven T–cell apoptosis to recovery from the disease. Finally, we speculate on the relevance of neuroimmune interactions in the pathogenesis of multiple sclerosis.     

How cancer hijacks the body’s homeostasis through the neuroendocrine system

During oncogenesis, cancer not only escapes the body’s regulatory mechanisms, but also gains the ability to affect local and systemic homeostasis. Specifically, tumors produce cytokines, immune mediators, classical neurotransmitters, hypothalamic and pituitary hormones, biogenic amines, melatonin, and glucocorticoids, as demonstrated in human and animal models of cancer. The tumor, through the release of these neurohormonal and immune mediators, can control the main neuroendocrine centers such as the hypothalamus, pituitary, adrenals, and thyroid to modulate body homeostasis through central regulatory axes. We hypothesize that the tumor-derived catecholamines, serotonin, melatonin, neuropeptides, and other neurotransmitters can affect body and brain functions. Bidirectional communication between local autonomic and sensory nerves and the tumor, with putative effects on the brain, is also envisioned. Overall, we propose that cancers can take control of the central neuroendocrine and immune systems to reset the body homeostasis in a mode favoring its expansion at the expense of the host.     

Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems

This review briefly summarizes a part of the relevant knowledge base of neuroimmunology, with particular emphasis on bidirectional neural-immune interactions. These complex systems interact at multiple levels. Both neuroendocrine (the primary hormonal pathway is hypothalamic-pituitary-adrenal axis) and neuronal (direct sympathetic innervation of the lymphoid organs) pathways are involved in the control of the humoral and cellular immune responses. Although, the recent evidence has been made on immunosuppressive effect of acetylcholine-secreting neurons of the parasympathetic nervous system. The immune system, in turn, influences the central nervous system primarily through cytokines. At the molecular level, neuro- and immune signal molecules (hormones, neurotransmitters, neuropeptides, cytokines) or their receptors are member of the same superfamily which enable the mutual neuroimmune communication. Most extensively studied are cytokine-neuropeptide/neurotransmitter interactions and the subcellular and molecular mechanisms of these interactions. At the system (neuroanatomical) level, advances in neural-immune communication have been made in the role of discrete brain areas related to emotionality. The immunoenhancement, including the antiviral and antitumor cytotoxic activity, related to the "brain reward system", limbic structures and neocortex, offers a new directions for therapy in immune disorders.     

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.     

Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression

The brain interprets experiences and translates them into behavioral and physiological responses. Stressful events are those which are threatening or, at the very least, unexpected and surprising, and the physiological and behavioral responses are intended to promote adaptation via a process called "allostasis. " Chemical mediators of allostasis include cortisol and adrenalin from the adrenal glands, other hormones, and neurotransmitters, the parasympathetic and sympathetic nervous systems, and cytokines and chemokines from the immune system. Two brain structures, the amygdala and hippocampus, play key roles in interpreting what is stressful and determining appropriate responses. The hippocampus, a key structure for memories of events and contexts, expresses receptors that enable it to respond to glucocorticoid hormones in the blood, it undergoes atrophy in a number of psychiatric disorders; it also responds to stressors with changes in excitability, decreased dendritic branching, and reduction in number of neurons in the dentate gyrus. The amygdala, which is important for "emotional memories, " becomes hyperactive in posttraumatic stress disorder and depressive illness, in animal models of stress, there is evidence for growth and hypertrophy of nerve cells in the amygdala. Changes in the brain after acute and chronic stressors mirror the pattern seen in the metabolic, cardiovascular, and immune systems, that is, short-term adaptation (allostasis) followed by long-term damage (allostatic load), eg, atherosclerosis, fat deposition obesity, bone demineralization, and impaired immune function. Allostatic load of this kind is seen in major depressive illness and may also be expressed in other chronic anxiety and mood disorders.     

Stress as a risk factor in the pathogenesis of rheumatoid arthritis

Stress is now recognized as an important risk factor in the pathogenesis of autoimmune rheumatic diseases (i.e. rheumatoid arthritis) by considering that the activation of the stress response system influences the close relationships existing between the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system and the immune system. The stress response results in the release of neurotransmitters (norepinephrine), hormones (cortisol) and immune cells which serve to send an efferent message from the brain to the periphery. Major life events lead to an intense release of stress mediators (large time integral of released neurotransmitters and hormones), whereas in minor life events, only short-lived surges of neurotransmitters and hormones are expected. Therefore, it is suggested that neurotransmitters such as norepinephrine or stress hormones such as cortisol might have different effects on immune/inflammatory responses at high and low concentrations present during short or extended periods of time, respectively. Long-lasting (chronic) stress may lead to proinflammatory effects because no adequate long-term responses of stress axes (anti-inflammatory) are to be expected.     

Receptor regulation in neuroendocrine-immune communication: current knowledge and future perspectives

Immune cells express receptors for every hormone or neurotransmitter we know so far. The neuroendocrine system signals to the immune system via the release of hormones and neurotransmitters that regulate cellular activity via these receptors. Much attention has been focused on the effect of glucocorticoids and catecholamines on the immune system. Glucocorticoids communicate with immune cells via glucocorticoid receptors of which the activity itself changes during immune activation. Many neuroendocrine mediators are ligands for G-protein coupled receptors on immune cells. Cytokines, oxygen-radicals, and catecholamines can influence the responsiveness of G-protein coupled receptors via decreasing the intracellular level of so-called G-protein coupled receptor kinases, of which the subtype GRK2 is highly expressed in immune cells. Therefore, changes in only one kinase can modulate the sensitivity of many receptors. We describe here that sensitivity of neuroendocrine receptors on immune cells is constantly regulated by inflammatory processes or chronic stress, which implies that not only the activity of the neuroendocrine system determines communication but that the sensitivity of receptors is a major factor in determining the final immune response. Finally, consequences of alterations in GRK2 during (neuro)-inflammatory diseases are discussed.     

Conceptual development of the immune system as a sixth sense

Understanding how and why the immune and nervous systems communicate in a bidirectional pathway has been fundamental to the development of the psychoneuroimmunology (PNI) field. This review will discuss some of the pivotal results that found the nervous and immune systems use a common chemical language for intra and inter-system communication. Specifically the nervous and immune systems produce a common set of peptide and nonpeptide neurotransmitters and cytokines that provides a common repertoire of receptors and ligands between the two systems. These studies led to the concept that through the sharing of ligands and receptors the immune system could serve as a sixth sense to detect things the body cannot otherwise hear, see, smell, taste or touch. Pathogens, tumors, and allergens are detected with great sensitivity and specificity by the immune system. As a sixth sense the immune system is a means to signal and mobilize the body to respond to these types of challenges. The paper will also review in a chronological manner some of the PNI-related studies important to validating the sixth sense concept. Finally, the review will suggest ways to apply the new found knowledge of the sixth sense to understanding a placebo effect and developing new therapeutic approaches for treatment of human diseases.     

Immune modulation of learning, memory, neural plasticity and neurogenesis

Over the past two decades it became evident that the immune system plays a central role in modulating learning, memory and neural plasticity. Under normal quiescent conditions, immune mechanisms are activated by environmental/psychological stimuli and positively regulate the remodeling of neural circuits, promoting memory consolidation, hippocampal long-term potentiation (LTP) and neurogenesis. These beneficial effects of the immune system are mediated by complex interactions among brain cells with immune functions (particularly microglia and astrocytes), peripheral immune cells (particularly T cells and macrophages), neurons, and neural precursor cells. These interactions involve the responsiveness of non-neuronal cells to classical neurotransmitters (e.g., glutamate and monoamines) and hormones (e.g., glucocorticoids), as well as the secretion and responsiveness of neurons and glia to low levels of inflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNFα, as well as other mediators, such as prostaglandins and neurotrophins. In conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, glia and other brain immune cells change their morphology and functioning and secrete high levels of pro-inflammatory cytokines and prostaglandins. The production of these inflammatory mediators disrupts the delicate balance needed for the neurophysiological actions of immune processes and produces direct detrimental effects on memory, neural plasticity and neurogenesis. These effects are mediated by inflammation-induced neuronal hyper-excitability and adrenocortical stimulation, followed by reduced production of neurotrophins and other plasticity-related molecules, facilitating many forms of neuropathology associated with normal aging as well as neurodegenerative and neuropsychiatric diseases.     

Involvement of dopamine in the progression of AIDS Dementia Complex

Summary. HIV compromises immunological functions. Immune responses are regulated to a great extent by several molecules such as cytokines, neurotransmitters and hormones which interact with different immune effector cells and ultimately mediate the homeostatic responses to disease. Among these mediators, dopamine plays an important role. In this article we review AIDS Dementia Complex (ADC) and describe lines of evidence implying increased dopamine availability as a potent mediator of neurologic deficits in HIV infection and a factor exhibiting adverse effects on the progression of ADC. Received March 1, 2001; accepted April 25, 2001     

The neurobiology of stress: from serendipity to clinical relevance

The hormones and other physiological agents that mediate the effects of stress on the body have protective and adaptive effects in the short run and yet can accelerate pathophysiology when they are over-produced or mismanaged. Here we consider the protective and damaging effects of these mediators as they relate to the immune system and brain. 'Stress' is a principle focus, but this term is rather imprecise. Therefore, the article begins by noting two new terms, allostasis and allostatic load that are intended to supplement and clarify the meanings of 'stress' and 'homeostasis'. For the immune system, acute stress enhances immune function whereas chronic stress suppresses it. These effects can be beneficial for some types of immune responses and deleterious for others. A key mechanism involves the stress-hormone dependent translocation of immune cells in the blood to tissues and organs where an immune defense is needed. For the brain, acute stress enhances the memory of events that are potentially threatening to the organism. Chronic stress, on the other hand, causes adaptive plasticity in the brain, in which local neurotransmitters as well as systemic hormones interact to produce structural as well as functional changes, involving the suppression of ongoing neurogenesis in the dentate gyrus and remodelling of dendrites in the Ammon's horn. Under extreme conditions only does permanent damage ensue. Adrenal steroids tell only part of the story as far as how the brain adapts, or shows damage, and local tissue modulators - cytokines for the immune response and excitatory amino acid neurotransmitters for the hippocampus. Moreover, comparison of the effects of experimenter-applied stressors and psychosocial stressors show that what animals do to each other is often more potent than what experimenters do to them. And yet, even then, the brain is resilient and capable of adaptive plasticity. Stress-induced structural changes in brain regions such as the hippocampus have clinical ramifications for disorders such as depression, post-traumatic stress disorder and individual differences in the aging process.     

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.     

Norepinephrine, dopamine and dexamethasone modulate discrete leukocyte subpopulations and cytokine profiles from human PBMC

The interplay between the immune and neuroendocrine systems is intense, with the cross-talk between these two systems increasing during stress circumstances. Stress events culminate with hormonal pathway activation elevating the plasma levels of glucocorticoids and catecholamines. The majority of the works evaluating the effects of stress hormones on immune cells have utilized in vivo animal models or clinical studies. This work evaluates the effects of norepinephrine, dopamine, dexamethasone, and the combination of norepinephrine and dexamethasone on cellular activation and expression of immunoregulatory cytokines and chemokines by human PBMC in vitro. Norepinephrine and dopamine increased lymphocyte activation accompanied by augmented Th1 and Th2 type cytokine production. Dexamethasone reduced cell activation and decreased frequencies of cytokine producing cells and chemokine production. The action of norepinephrine together with dexamethasone resulted in immunosupression. The observed effects of hormones and neurotransmitters on leukocyte subsets likely underlie their immunomodulatory action in vivo.     

The immune-hypothalamo-pituitary-adrenal axis and autoimmunity.

Immunoendocrinology is a rapidly expanding field, uncovering numerous bilateral interactions between the immune system and neuroendocrine circuits. Various hormones and neurotransmitters appear to modulate cells of the immune system and likewise cytokines control the function of neuroendocrine system. In the present paper, we discuss some lines of evidence indicating that an immunoendocrine feedback loop, which we term 'immune-hypothalamo-pituitary-adrenal system' is an integral part of the regulation of self tolerance. The finding that pathology of this immunoendocrine feedback loop is related to development of autoimmunity may lead to new prophylactic and therapeutic strategies.     

Conditioned immunomodulation: research needs and directions

Considering the brief time that psychoneuroimmunology has existed as a bona fide field of research, a great deal of data has been collected in support of the proposition that homeostatic mechanisms are the product of an integrated system of defenses of which the immune system is a critical component. It is now clear that immune function is influenced by autonomic nervous systems activity and by the release of neuroendocrine substances from the pituitary. Conversely, cytokines and hormones released by an activated immune system influence neural and endocrine processes. Regulatory peptides and receptors, once confined to the brain, are expressed by both the nervous and immune systems enabling each system to monitor and modulate the activities of the other. It is hardly surprising, then, that immunologic reactivity can be influenced by stressful life experiences or by Pavlovian conditioning.     

Cytokines in schizophrenia and the effects of antipsychotic drugs

Growing evidence suggests that the immune, endocrine, and nervous systems interact with each other through cytokines, hormones, and neurotransmitters. The activation of the cytokine systems may be involved in the neuropathological changes occurring in the central nervous system (CNS) of schizophrenic patients. Numerous studies report that treatment with antipsychotic drugs affects the cytokine network. Hence, it is plausible that the influence of antipsychotics on the cytokine systems may be responsible for their clinical efficacy in schizophrenia. This article reviews current data on the cytokine-modulating potential of antipsychotic drugs. First, basic information on the cytokine networks with special reference to their role in the CNS as well as an up-to-date knowledge of the cytokine alterations in schizophrenia is outlined. Second, the hitherto published studies on the influence of antipsychotics on the cytokine system are reviewed. Third, the possible mechanisms underlying antipsychotics' potential to influence the cytokine networks and the most relevant aspects of this activity are discussed. Finally, limitations of the presented studies and prospects of future research are delineated.     

Immune-neuroendocrine circuits: integrative role of cytokines.

Several efficient autoregulatory mechanisms confer a certain degree of autonomy to the immune system. However, increasing evidence shows that immune processes operate in a coordinated fashion with other body systems. In this article, we discuss concepts and facts concerning interactions between immune and neuroendocrine mechanisms. There are clear examples that immune cells can be influenced by hormones, neurotransmitters, and neuropeptides and also by alterations in brain functions. Conversely, immune-derived products such as lymphokines and monokines can affect endocrine, autonomic, and central mechanisms. Neuroendocrine responses occur during the activation of the immune system. These responses can be elicited by innocuous antigens; they can also be detected during pathological conditions involving immune activation, and in many cases are dissociable from the effects of the disease itself and from the stress of being sick. On this basis, we emphasize the multidirectional nature of the communication processes between the immune, endocrine, and nervous systems. The role of lymphokines and monokines as messengers able to convey information to neuro and endocrine structures about the present state of activity of the immune system is stressed. The relevance of immune-neuroendocrine interactions for immunoregulation and host defenses is discussed as well as the active role of the immune system in mediating metabolic and homeostatic adjustments or derangements during the course of certain infectious, inflammatory, and neoplastic processes. The evidence available suggests that complex immune-neuroendocrine networks operate under both physiological and pathological conditions.     

The Immune System and the Role of Inflammation in Perinatal Depression

Major depression during pregnancy is a common psychiatric disorder that arises from a complex and multifactorial etiology. Psychosocial stress, sex, hormones, and genetic vulnerability increase the risk for triggering mood disorders. Microglia and toll-like receptor 4 play a crucial role in triggering wide and varied stress-induced responses mediated through activation of the inflammasome; this leads to the secretion of inflammatory cytokines, increased serotonin metabolism, and reduction of neurotransmitter availability along with hypothalamic–pituitary–adrenal axis hyperactivity. Dysregulation of this intricate neuroimmune communication network during pregnancy modifies the maternal milieu, enhancing the emergence of depressive symptoms and negative obstetric and neuropsychiatric outcomes. Although several studies have clearly demonstrated the role of the innate immune system in major depression, it is still unclear how the placenta, the brain, and the monoaminergic and neuroendocrine systems interact during perinatal depression. Thus, in the present review we describe the cellular and molecular interactions between these systems in major depression during pregnancy, proposing that the same stress-related mechanisms involved in the activation of the NLRP3 inflammasome in microglia and peripheral myeloid cells in depressed patients operate in a similar fashion in the neuroimmune placenta during perinatal depression. Thus, activation of Toll-like receptor 2 and 4 signaling and the NLRP3 inflammasome in placental immune cells may promote a shift of the Th1/Th2 bias towards a predominant Th1/Th17 inflammatory response, associated with increased secretion of pro-inflammatory cytokines, among other secreted autocrine and paracrine mediators, which play a crucial role in triggering and/or exacerbating depressive symptoms during pregnancy.