Anterior pituitary hormones, stress, and immune system homeostasis

An extensive, and controversial, literature concluding that prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid hormones are critical immunoregulatory factors has accumulated. However, recent studies of mice deficient in the production of these hormones or expression of their receptors indicate that there are only a few instances in which these hormones are required for lymphocyte development or antigen responsiveness. Instead, a case is made that their primary role is to counteract the effects of negative immunoregulatory factors, such as glucocorticoids, which are produced when the organism is subjected to major stressors. The immunoprotective actions of PRL, GH, IGF-I, and/or thyroid hormones in these instances may ensure immune system homeostasis and reduce the susceptibility to stress-induced disease. These immuno-enhancing effects could be exploited clinically in instances where the immune system is depressed due to illness or various treatment regimens.     

The stress response and immune system share,borrow, and reconfigure their physiological network elements: Evidence from the insects

The classic biomedical view is that stress hormone effects on the immune system are largely pathological, especially if the stress is chronic. However, more recent interpretations have focused on the potential adaptive function of these effects. This paper examines stress response-immune system interactions from a physiological network perspective, using insects because of their simpler physiology. For example, stress hormones can reduce disease resistance, yet activating an immune response results in the release of stress hormones in both vertebrates and invertebrates. From a network perspective, this phenomenon is consistent with the ‘sharing’ of the energy-releasing ability of stress hormones by both the stress response and the immune system. Stress-induced immunosuppression is consistent with the stress response ‘borrowing’ molecular components from the immune system to increase the capacity of stress-relevant physiological processes (i.e. a trade off). The insect stress hormones octopamine and adipokinetic hormone can also ‘reconfigure’ the immune system to help compensate for the loss of some of the immune system's molecular resources (e.g. apolipophorin III). This view helps explain seemingly maladaptive interactions between the stress response and immune system. The adaptiveness of stress hormone effects on individual immune components may be apparent only from the perspective of the whole organism. These broad principles will apply to both vertebrates and invertebrates.     

Effects of testosterone and corticosterone on immunocompetence in the zebra finch

The original immunocompetence handicap hypothesis (ICHH) suggested that testosterone has a handicapping effect in males by both promoting the development of sexual signals and suppressing immune function. A modified version, the stress-linked ICHH, has recently proposed that testosterone is immunosuppressive indirectly by increasing production of corticosterone. To test both the original and stress-mediated versions of the ICHH, we implanted male zebra finches taken from lines selected for divergent maximum stress-induced levels of corticosterone (high, low and control) with either empty or testosterone-filled implants. Their humoral and cell-mediated immune responses were then assessed by challenge with diphtheria:tetanus vaccine and phytohemagglutinin respectively. We found no effect of the hormone manipulations on either PHA or tetanus antibody responses, but found a significant interaction between titers of both testosterone and corticosterone on diphtheria secondary antibody response; antibody response was greatest in individuals with high levels of both hormones. There was also a significant interactive effect between testosterone treatment group and corticosterone titer on body mass; the body mass of males in the elevated testosterone treatment group decreased with increasing corticosterone titer. These results suggest that, contrary to the assumption of the stress-mediated version of the ICHH, high plasma levels of corticosterone are not immunosuppressive, but are in fact immuno-enhancing in the presence of high levels of plasma testosterone. Equally, the central assumption of the ICHH that testosterone is obligately immunosuppressive is also not supported. The same individuals with the highest levels of both hormones and consequently the most robust antibody response also possessed the lowest body mass.     

Trypanosoma cruzi: plasma corticosterone after repetitive stress during the acute phase of infection

An increased level of plasma corticosterone is one manifestation of severe environmental or physiologic stress. The stress response mediated by the hypothalamic-pituitary-adrenal axis is already known to suppress immunoglobulin production and to impair immune function, but there are few studies relating stress and plasma corticosterone to the outcome of Trypanosoma cruzi infection. In this study, male Wistar rats were infected with the Y strain of T. cruzi and then subjected to repetitive stress by exposure to ether vapor for 1min twice a day during the acute phase of infection. Stressed animals showed decreased lytic antibody activity and lowered levels of peritoneal macrophages. Despite an increase in the weight of the spleen, histological analyses demonstrated tissue alterations, the presence of amastigote nests, and a complete absence of activated lymphoid follicles. These results suggest that stress-induced increases in plasma corticosterone can suppress the immune response and worsen tissue injury during the acute phase of T. cruzi infection.     

Effects of salinity on the immune response of an ‘osmotic generalist’ bird

Salt stress can suppress the immune function of fish and other aquatic animals, but such an effect has not yet been examined in air-breathing vertebrates that frequently cope with waters (and prey) of contrasting salinities. We investigated the effects of seawater salinity on the strength and cost of mounting an immune response in the dunlin Calidris alpina, a long-distance migratory shorebird that shifts seasonally from freshwater environments during the breeding season to marine environments during migration and the winter period. Phytohaemagglutinin (PHA)-induced skin swelling, basal metabolic rate (BMR), body mass, fat stores, and plasma ions were measured in dunlins acclimated to either freshwater or seawater (salinity: 0.3 and 35.0 ‰, respectively). Seawater-acclimated dunlins mounted a PHA-induced swelling response that was up to 56 % weaker than those held under freshwater conditions, despite ad libitum access to food. Freshwater-acclimated dunlins significantly increased their relative BMR 48 h after PHA injection, whereas seawater-acclimated dunlins did not. However, this differential immune and metabolic response between freshwater- and seawater-acclimated dunlins was not associated with significant changes in body mass, fat stores or plasma ions. Our results indicate that the strength of the immune response of this small-sized migratory shorebird was negatively influenced by the salinity of marine habitats. Further, these findings suggest that the reduced immune response observed under saline conditions might not be caused by an energy or nutrient limitation, and raise questions about the role of osmoregulatory hormones in the modulation of the immune system.     

The thymus and the acute phase response.

The thymus is a primary lymphoid organ with both endocrine and immune functions. There is a large body of evidence indicating the existence of a complex neuroendocrine control of the thymus physiology. This is supported by the historic observation that the thymus becomes involuted during the response to stress. The thymus is dramatically affected by the acute phase response (APR), a systemic reaction to tissue injury and/or infection accompanied by profound neuroendocrine and metabolic changes. The APR comprises alterations in behavior, body temperature, and production and release of cytokines, particularly interleukin (IL)-1, IL-6 and TNFalpha, and glucocorticoids (GCs) and is characterized by suddenly increased production of so-called acute phase proteins (APPs). The stimulation of APR activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the suppression of specific immunity, which might serve to protect the organism from adverse immune reactions; the immunostimulatory hormones (e.g., PRL, GH, IGF-1) are suppressed, whereas the production of APPs in the liver is stimulated by IL-6, catecholamines and GCs. The most striking effect of the latter on the immune system is the induction of apoptosis in the thymus. In concert with GCs, elevated levels of catecholamines also selectively suppress immune response mechanisms. APR may be regarded as an emergency response that represents a switch of the host defense from the adaptive immune response which is slow to develop and is commanded by the thymus and T-lymphocytes to a less specific, but more rapid and intense reaction. Here we discuss the immunoregulatory changes during the APR with a special emphasis on the role of thymus in this process.     

The effects of the stress response on immune function in invertebrates: An evolutionary perspective on an ancient connection

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Stress-induced changes in immune function occur in animals across phyla, and these effects are usually immunosuppressive. The function of this immunomodulation remains elusive; however, the existence of specialized receptors on immune cells suggests that it is adaptive. A comparative approach may provide a useful perspective. Although invertebrates have simpler endocrine/neuroendocrine systems and immune systems than vertebrates, they have robust stress responses that include the release of stress hormones/neurohormones. Stress hormones modify immune function in mollusks, insects, and crustaceans. As in vertebrates, the effects of stress hormones/neurohormones on invertebrate immune function are complex, and are not always immunosuppressive. They are context-, stressor-, time- and concentration-dependent. Stress hormone effects on invertebrate immune function may help to re-align resources during fight-or-flight behavior. The data are consistent with the hypothesis that stress hormones induce a reconfiguration of networks at molecular, cellular and physiological levels that allow the animal to maintain optimal immunity as the internal environment changes. This reconfiguration enhances some immune functions while suppressing others. Knowing the molecular details of these shifts will be critical for understanding the adaptive function of stress hormones on immune function.     

Effects of immune activation and glucocorticoid administration on feather growth in greenfinches

Elevation of glucocorticoid (GC) hormone levels is an integral part of stress response (as well as its termination) and immunomodulation. These hormones are also responsible for mobilizing energy stores by stimulation of gluconeogenesis and inhibition of protein synthesis. Elevation of GCs is thus incompatible with other protein-demanding processes, such as moult. Previous studies have shown that chronic elevation of GC hormones suppresses feather growth. Here, we asked whether similar effect would also occur in the case of acute GC elevation and induction of an inflammatory response by foreign antigen. We performed an experiment on captive wild-caught greenfinches (Carduelis chloris) injecting birds with phytohaemagglutinin (PHA) and dexamethasone (DEX) in a factorial design. To assess the possible somatic impacts of these manipulations, we removed one of the outermost tail feathers before the experiment and measured mass and rachis diameter and length of the replacement feathers grown in captivity. Immunostimulation by PHA reduced rachis length, but did not affect feather mass or rachis diameter. Single injection of a synthetic GC hormone DEX significantly reduced all three parameters of feather size. Altogether, these findings demonstrate the sensitivity of feather growth to manipulation of immune and adrenal functions. Our results corroborate the somatic costs of immune activation and suggest that even a short-term elevation of GC hormones may induce long-term somatic costs with a potential impact on fitness. Our findings also imply that a single injection of DEX, frequently used as a diagnostic tool, can have lasting effects and researchers must consider this when designing experiments.     

Regulation of proliferation, invasion and growth factor synthesis in breast cancer by steroids

Endogenous ovarian estrogens and progestins appear to play a critical role in the development and progression of breast cancer. Local productions of growth factors probably also contribute to malignant proliferation, while production and activation of collagenolytic enzymes may be equally critical for local invasive processes. The current review focuses on characterization of growth factor-receptor systems operant in normal and malignant breast epithelium. In addition, the determinants of local invasion are reviewed: attachment, modality, and proteose secretion. Finally, data are discussed concerning the regulation of both proliferation and invasion by hormones and antihormonal agents in hormone-dependent breast cancer. The results suggest new potential pharmacologic targets to explore to suppress onset and progression of breast cancer.     

A hassle a day may keep the doctor away: stress and the augmentation of immune function

Stress may be defined as a sequence of events, that begins witha stimulus (stressor), that is recognized by the brain (stressperception), and which results in the activation of physiologicfight/flight/fright systems within the body (stress response).Many evolutionary selection pressures are stressors, and oneof the primary functions of the brain is to perceive stress,warn the body of danger, and enable an organism to respond.We hypothesized that under acute conditions, just as the stressresponse prepares the cardiovascular and musculoskeletal systemsfor fight or flight, it may also prepare the immune system forchallenges (e.g., wounding) which may be imposed by a stressor(e.g., an aggressor). Initial studies showed that acute (2h)stress induced a significant trafficking of immune cells tothe skin. Since the skin is an organism's major protective barrier,we hypothesized that this leukocyte redistribution may serveto enhance skin immunity during acute stress. We tested thishypothesis using the delayed type hypersensitivity (DTH) reaction,which mediates resistance to various infectious agents, as amodel for skin immune function. Acute stress administered immediatelybefore antigen exposure significantly enhanced skin DTH. Adrenalectomy(ADX) eliminated the stress-induced enhancement of DTH whileadministration of physiological doses of corticosterone and/orepinephrine to ADX animals enhanced skin DTH in the absenceof stress. These studies showed that changes in leukocyte distributionand circulating stress hormones are systemic mediators of theimmunoenhancing effects of acute stress. We recently identifiedgamma interferon as a local cytokine mediator of a stress-inducedimmunoenhancement. Our results suggest that during acute stressthe brain sends preparatory warning signals to the immune systemjust as it does to other fight/flight systems of the body.     

Chronic stress influences the immune system through the thyroid axis

The aim of the present work was to analyze the effect of chronic stress on thyroid axis and its influence on the immune response. For this purpose a murine model of chronic stress was developed to evaluate and to correlate thyroid hormone levels with humoral alloimmune response. Results show a reduction in serum levels of thyroid hormones, specially a significant decrease in serum levels of triiodotyronine (T3) in stressed animals. On the other hand, alloimmunization was not able to induce an early increment in T3 and thyroxine (T4) levels as it was previously reported in normal animals. In addition, lower titers of alloantibodies were obtained in animals under stress conditions as compared to normal mice. The sustitutive T4 treatment in stressed animals increased significantly alloantibody production as well as the early increment in thyroid hormones after antigenic challenge. These findings suggest that chronic stress induces an alteration of the function of thyroid axis that alters the immune response.     

Special feature for the Olympics: effects of exercise on the immune system: effects of exercise on the immune system in the elderly population

Immunosenescence is characterized by impaired cellular immune function concomitant with increased inflammatory activity. Immune dysfunction is associated with increased mortality risk in elderly people. An important part of human ageing is characterized by a decline in the ability of individuals to adapt to environmental stress. Exercise has been suggested as a prototype for studying the effects of stress factors on the cellular immune system. Studies of interactions between an acute bout of exercise and immune function may be a useful and an ethically acceptable tool to investigate cell trafficking, immune mobilization/deficiency and the acute phase response during physical stress situations in relation to human ageing. Elderly humans have a preserved ability to recruit T lymphocytes and NK cells in response to an acute bout of exercise. Physical exercise training programs do not result in major restoration of the senescent immune system in humans. However, highly conditioned elderly humans seem to have a relatively better preserved immune system, although it is not possible to conclude if this is linked to training or other lifestyle-related factors.     

Raised cortisol:DHEAS ratios in the elderly after injury: potential impact upon neutrophil function and immunity

The detrimental effect of stress on the immune response increases with age, though the mechanisms responsible are not fully understood. The physiological response to stress is regulated in part by the adrenocortical system. Adrenal hormones dehydroepiandrosterone sulphate (DHEAS) and cortisol have opposing effects on the innate immune system, DHEAS enhances while cortisol suppresses immunity and the molar ratio of cortisol to DHEAS increases with age. We found that elderly hip fracture patients produced a robust neutrophilia after injury, but circulating neutrophils showed an impaired antibacterial response. We therefore proposed that adrenocortical hormones mediate the heightened immunosuppression seen in the elderly after injury. We examined neutrophil function and adrenocortical hormone levels in elderly (> 65 years) hip fracture patients and age-matched healthy controls. Thirteen out of 35 elderly patients acquired infections following hip fracture. Neutrophil superoxide production was lower in elderly hip fracture patients compared with controls (P < 0.005) and lower in patients who acquired infection following injury compared with those who did not (P < 0.05). Serum cortisol:DHEAS ratio was higher in elderly hip fracture patients (0.56 +/- 0.38) compared with either age-matched controls (0.36 +/- 0.21; P < 0.05) or young fracture patients (0.087 +/- 0.033; P < 0.0001). Moreover, cortisol: DHEAS was increased in elderly patients who succumbed to infection compared with those who did not (0.803 +/- 0.42 vs. 0.467 +/- 0.28; P < 0.02). In vitro cortisol significantly decreased neutrophil superoxide generation (P < 0.05) and this was prevented by coincubation with DHEAS. We propose that increased cortisol:DHEAS ratios may contribute to reduced immunity following physical stress in the elderly.     

Effects of elevated egg corticosterone levels on behavior, growth, and immunity of yellow-legged gull (Larus michahellis) chicks

Eggs of vertebrates contain steroid hormones of maternal origin that may influence offspring performance. Recently, it has been shown that glucocorticoids, which are the main hormones mediating the stress response in vertebrates, are transmitted from the mother to the egg in birds. In addition, mothers with experimentally elevated corticosterone levels lay eggs with larger concentrations of the hormone, which produce slow growing offspring with high activity of the hypothalamo-adrenal axis under acute stress. However, the effects and function of transfer of maternal corticosterone to the eggs are largely unknown. In the present study, we injected corticosterone in freshly laid eggs of yellow-legged gulls (Larus michahellis), thus increasing the concentration of the hormone within its natural range of variation, and analyzed the effect of manipulation on behavioral, morphological, and immune traits of the offspring in the wild. Eggs injected with corticosterone had similar hatching success to controls, but hatched later. Mass loss during incubation was greater for corticosterone-treated eggs, except for the last laid ones. Corticosterone injection reduced rate and loudness of late embryonic vocalizations and the intensity of chick begging display. Tonic immobility response, reflecting innate fearfulness, was unaffected by hormone treatment. Elevated egg corticosterone concentrations depressed T-cell-mediated immunity but had no detectable effects on humoral immune response to a novel antigen, viability at day 10, or growth. Present results suggest that egg corticosterone can affect the behavior and immunity of offspring in birds and disclose a mechanism mediating early maternal effects whereby stress experienced by females may negatively translate to offspring phenotypic quality.     

Stress physiology as a predictor of survival in Galapagos marine iguanas

Although glucocorticoid hormones are considered important physiological regulators for surviving adverse environmental stimuli (stressors), evidence for such a role is sparse and usually extrapolated from glucocorticoid effects under laboratory, short-term and/or non-emergency conditions. Galápagos marine iguanas (Amblyrhynchus cristatus) provide an excellent model for determining the ultimate function of a glucocorticoid response because susceptibility to starvation induced by El Niño conditions is essentially their only major natural stressor. In a prospective study, we captured 98 adult male marine iguanas and assessed four major components of their glucocorticoid response: baseline corticosterone titres; corticosterone responses to acute stressors (capture and handling); the maximal capacity to secrete corticosterone (via adrenocorticotropin injection); and the ability to terminate corticosterone responses (negative feedback). Several months after collecting initial measurements, weak El Niño conditions affected the Galápagos and 23 iguanas died. The dead iguanas were typified by a reduced efficacy of negative feedback (i.e. poorer post-stress suppression of corticosterone release) compared with surviving iguanas. We found no prior differences between dead and alive iguanas in baseline corticosterone concentrations, responses to acute stressors, nor in capacity to respond. These data suggest that a greater ability to terminate a stress response conferred a survival advantage during starvation.     

Lactation and resource limitation affect stress responses,thyroid hormones,immune function,and antioxidant capacity of sea otters (Enhydra lutris)

Lactation is the most energetically demanding stage of reproduction in female mammals. Increased energetic allocation toward current reproduction may result in fitness costs, although the mechanisms underlying these trade‐offs are not well understood. Trade‐offs during lactation may include reduced energetic allocation to cellular maintenance, immune response, and survival and may be influenced by resource limitation. As the smallest marine mammal, sea otters (Enhydra lutris) have the highest mass‐specific metabolic rate necessitating substantial energetic requirements for survival. To provide the increased energy needed for lactation, female sea otters significantly increase foraging effort, especially during late‐lactation. Caloric insufficiency during lactation is reflected in the high numbers of maternal deaths due to End‐Lactation Syndrome in the California subpopulation. We investigated the effects of lactation and resource limitation on maternal stress responses, metabolic regulation, immune function, and antioxidant capacity in two subspecies of wild sea otters (northern: E. l. nereis and southern: E. l. kenyoni) within the California, Washington, and Alaska subpopulations. Lactation and resource limitation were associated with reduced glucocorticoid responses to acute capture stress. Corticosterone release was lower in lactating otters. Cortisol release was lower under resource limitation and suppression during lactation was only evident under resource limitation. Lactation and resource limitation were associated with alterations in thyroid hormones. Immune responses and total antioxidant capacity were not reduced by lactation or resource limitation. Southern sea otters exhibited higher concentrations of antioxidants, immunoglobulins, and thyroid hormones than northern sea otters. These data provide evidence for allocation trade‐offs during reproduction and in response to nutrient limitation but suggest self‐maintenance of immune function and antioxidant defenses despite energetic constraints. Income‐breeding strategists may be especially vulnerable to the consequences of stress and modulation of thyroid function when food resources are insufficient to support successful reproduction and may come at a cost to survival, and thereby influence population trends.     

Effect of stress on the activity of the hypothalamic-pituitary-gonadal axis: peripheral and central mechanisms.

This article reviews the mechanisms believed to mediate stress-induced inhibition of reproductive functions and the anatomical sites at which these effects take place. Particular emphasis is placed on the potential modulating role of hormones or neurotransmitters released during stress. At the level of the gonads, adrenal corticoids, pro-opiomelanocortin (POMC)-like peptides, and corticotropin-releasing factor (CRF) are reported to interfere with the stimulatory action of gonadotropins on sex steroid-producing cells. Increased circulating corticosteroid levels may also decrease pituitary responsiveness to GnRH. There is, however, increasing evidence that these mechanisms are primarily involved in mediating the effects of prolonged stress, but not those of an acute stimulus. In contrast, a variety of hormones or neurotransmitters, including CRF, POMC peptides, and biogenic amines act within the brain to mediate the inhibitory influence of both acute and prolonged stresses on reproductive function.     

Immuno-enhancing actions of carnosine and homocarnosine

Immuno-enhancing actions of carnosine, beta-alanine, homocarnosine, and gamma-aminobutyric acid were studied in ddY mice by evaluating plaque-forming cell reaction against sheep red blood cells. Animals were administered the test agents in prior to, or simultaneously with, various treatments that are known to reduce immune function such as administration of the anti-tumor agents, mitomycin C and 5-fluorouracil, immunosuppressant cyclophosphamide, antiinflammatory agent hydrocortisone, or cancer implantation and gamma-irradiation. Experiments were performed also in aged mice with reduced immune function. The administration of these drugs showed non-specific immuno-enhancing effects under all conditions examined and on all cell groups that may have been affected by these immunosuppressive stimulus.     

Cues to sex- and stress-hormones in the human male face: functions of glucocorticoids in the immunocompetence handicap hypothesis

The stress-linked version of the immunocompetence handicap hypothesis has been proposed to account for inconsistencies in relationships between testosterone and immune response. The model has received some support from studies demonstrating roles of stress hormones in relationships between testosterone, immune function and secondary sexual ornamentation. Such work, however, has relied on artificial elevation of testosterone so may not reflect relationships in natural populations. We created human male facial stimuli on the basis of naturally co-occurring levels of salivary testosterone and the stress hormone cortisol. In Study 1 we tested female preferences for male faces with cues to combinations of the hormones across the menstrual cycle, and in Study 2 we tested perceptions of health and dominance in a novel set of facial stimuli. Females preferred cues to low cortisol, a preference that was strongest during the fertile phase of the menstrual cycle. The effects of cortisol on attractiveness and perceived health and dominance were contingent upon level of testosterone: the effects of the stress hormone were reduced when testosterone was high. We propose explanations for our results, including low cortisol as a cue to a heritable component of health, attractiveness as a predictor of low social-evaluative threat (and, therefore, low baseline cortisol) and testosterone as a proxy of male ability to cope efficiently with stressors.     

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.