Neuroendocrine-immune Interactions Research Articles

Interleukin-6 is an afferent signal to the hypothalamo-pituitary-adrenal axis during local inflammation in mice.

The cytokines IL-1 and IL-6 are able to induce prostaglandin (PG)-dependent activation of the hypothalamo-pituitary-adrenal axis (HPAA) and are thought to play key roles in immune-neuroendocrine interactions during inflammation. The present study shows that inflammation induced by im injection of turpentine (TPS) in the hind limb of mice causes an increase in the plasma concentration of IL-6, but not that of IL-1 alpha or IL-1 beta, together with a prolonged (>18-h) activation of the HPAA. IL-6 plays a causal role in the TPS-induced elevation in HPAA activity, because the sustained (8-18 h) increases in 1) plasma corticosterone, 2) plasma ACTH, and 3) induction of c-Fos in the hypothalamic paraventricular nucleus are all markedly blunted in IL-6-deficient (IL-6(-/-)) mice. Peripheral administration of a neutralizing IL-6 antiserum inhibited the plasma corticosterone response of normal (C57BL/6) mice to hind limb inflammation to an extent similar to that seen in IL-6(-/-) mice, suggesting that the IL-6 responsible for the increased HPAA activity is produced, or acts, on the blood side of the blood-brain barrier. We also show that IL-6 in the circulation is induced almost exclusively at the local inflammatory site, where IL-1 beta is produced. Induction of IL-6 and activation of the HPAA are dependent upon prior activation of an IL-1 type I receptor, as both are inhibited in type I IL-1 receptor-deficient mice. Furthermore, hind limb inflammation induced cyclooxygenase-2 protein expression around the cerebrovasculature of normal (IL-6(+/+)), but not IL-6(-/-), mice. Based on these data, we propose that IL-6 is produced at the local inflammatory site under the control of IL-1 beta and is the circulating afferent signal that is in part responsible for elevated HPAA activity, possibly acting via eicosanoid production within the cerebrovasculature.

Neuroendocrine immune interactions in health and disease

The purpose of this paper is to review ways in which the neurohormonal system can interact with the immune system and to outline the main mechanisms which are involved in this interaction. Experimental as well as clinical evidence is presented to support the existence of a close interaction and bi-directional communication between the central nervous and immune systems. The role of major endocrine mechanisms and hormones is discussed. The evidences from experimental work to support the roles of the nervous system with neurotransmitters, the endocrine system with hormones, and the immune system with cytokines are presented. Aging, depression and cancer have a high degree of co-association and share mechanisms which result in cellular immune deficiency. Hormone therapy, zinc replenishment, antidepressants, immunomodulators like MDP act on these pathways to upregulate and improve cellular immunity. The authors believe that the central nervous system (CNS)–immune interaction is an important new frontier to be considered for new combination therapy in diseases with cellular immune deficiency such as cancer particularly in the aged with depression.

Neuroendocrine-Immune Interactions and Starvation in Mucosal Immunity and Mucosal Inflammation

Mutual communication among the immune, neuroendocrine and metabolic systems is essential for the maintenance of gastrointestinal mucosal function. A unique barrier system by the mucosal immune system handles a myriad of infectious and food antigens, while the neuroendocrine system interplays with the immune system in the intestinal mucosa. The close relation between these two systems is associated with the pronounced effects of stress and metabolic changes.

Stress-induced augmentation of immune function—The role of stress hormones, leukocyte trafficking, and cytokines

Delayed-type hypersensitivity (DTH) reactions represent cell-mediated immune responses that exert important immunoprotective (resistance to viruses, bacteria, and fungi) or immunopathological (allergic or autoimmune hypersensitivity) effects. We initially utilized the skin DTH response as an experimental in vivo model to study neuro–endocrine-immune interactions in rodents. We hypothesized that just as an acute stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges which may be imposed by a stressor. The skin DTH model allowed us to examine the effects of stress at the time of primary and secondary exposure to antigen. Studies showed that acute (2 h) stress experienced before primary or secondary antigen exposure induces a significant enhancement of skin DTH. Importantly, this enhancement involved innate as well as adaptive immune mechanisms. Adrenalectomy eliminated the stress-induced enhancement of DTH. Acute administration of physiological (stress) concentrations of corticosterone and/or epinephrine to adrenalectomized animals enhanced skin DTH. Compared with controls, DTH sites from acutely stressed or hormone-injected animals showed significantly greater erythema and induration, numbers of infiltrating leukocytes, and levels of cytokine gene expression. In contrast to acute stress, chronic stress was immunosuppressive. Chronic exposure to corticosterone, or acute exposure to dexamethasone significantly suppressed skin DTH. These results suggest that during acute stress, endogenous stress hormones enhance skin immunity by increasing leukocyte trafficking and cytokine gene expression at the site of antigen entry. While these results are discussed from a mechanistic and clinical relevance perspective, it is acknowledged that much work remains to be done to elucidate the precise mechanisms mediating these bi-directional effects of stress and stress hormones and their clinical ramifications.

Neuroendocrine-Immune Interactions EuroConference on Molecular Mechanisms and Clinical Relevance of Brain-Immune Communication San Feliu de Guixols, Spain, 5-10 October 2002.

Neuroendocrine-Immune Interactions EuroConference on Molecular Mechanisms and Clinical Relevance of Brain-Immune Communication San Feliu de Guixols, Spain, 5-10 October 2002.

Neuroendocrine-Immune Interactions EuroConference on Molecular Mechanisms and Clinical Relevance of Brain-Immune Communication San Feliu de Guixols, Spain, 5-10 October 2002

Neuroendocrine-Immune Interactions EuroConference on Molecular Mechanisms and Clinical Relevance of Brain-Immune Communication San Feliu de Guixols, Spain, 5-10 October 2002

Neuroendocrine–immune interactions in fish: a role for interleukin-1

Bi-directional communication between the hypothalamus–pituitary–adrenal (HPA)-axis and the sympathetic nervous system with the immune system is crucial to ensure homeostasis. Shared use of ligands and especially receptors forms a key component of this bi-directional interaction. Glucocorticoids (GC), the major end products of the HPA-axis differentially modulate immune function. Cytokines, especially interleukin-1 (IL-1), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), ensure immune signalling to the neuroendocrine system. In addition, hormones from leukocyte origin such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and β-endorphin, as well as centrally synthesised and secreted cytokines, contribute to the communication network. In teleost fish cortisol is the major product of the hypothalamus–pituitary–interrenal (HPI)-axis which is the teleost equivalent of the HPA-axis. Moderate and substantial increases in cortisol during stressful circumstances negatively affect B-lymphocytes, whereas rescue of neutrophilic granulocytes may support innate immunity. Recent elucidation of lower vertebrate cytokine sequences has facilitated research into neuroendocrine–immune interactions in teleosts and the first evidence for a significant function of interleukin-1 in the bi-directional communication is discussed.

Somatostatin-like immunoreactivity (SLIR) in rat harderian and meibomian glands and glands of Zeis.

In many species serous lacrimal glands bind sex hormones and prolactin, have cells making immunoglobulins and growth factors, and contain nerve fibers having peptides such as VIP, NPY, and Substance P.1 Because the latter neuropeptides also occur in the sebaceous meibomian gland,2 the present study sought to determine the possible presence and cellular localization of somatostatin (SOM) in the three lipid-containing3, 4 lacrimal glands of the rat. Its existence might affect neuroendocrine-immune system interactions,5 presumably diminishing them because SOM inhibits lymphocyte proliferation.6

CORTICOTROPIN‐RELEASING HORMONE (CRH) MRNA EXPRESSION IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS (PVN) DURING EXPERIMENTAL COLITIS IN THE RAT

Background Neuroendocrine–immune interactions can influence processes arising from the brain, and there is evidence that the central nervous system may amplify or modulate aspects of intestinal inflammation through alterations of the autonomic nervous system activity and/or stimulation of the hypothalamic–pituitary–adrenal (HPA) axis (American Journal of Physiology 276: G1027, 1999). But the effect of the colitis itself on the HPA axis remains unclear.Aim To investigate the effect of experimental colitis on the HPA‐axis, especially on CRH mRNA expression in the PVN, plasma adenocorticotropin (ACTH) and corticosterone (CORT) level.Methods Under isoflurane anesthesia, male SD rats (250–300 g) were induced to colitis by intracolonic administration of 0.2 mL of 50% ethanol (v/v) containing 20 mg of 2,4,6‐trinitrobenzenesulfonic acid (TNBS). In the first experiment, rats were sacrificed before and on days 1, 3, 7 and 14 after induction of colitis, and CRH mRNA levels in the PVN were quantified by in situ hybridization, plasma ACTH and CORT levels were measured by radioimmunoassay, and the colonic damage was assessed by measurement of colonic myeloperoxidase (MPO) activity. In the second experiment, rats were adrenalectomized bilaterally and corticosterone pellet was implanted subcutaneously (ADX + CORT). On day 3 after ADX + CORT, rats were infused TNBS (TNBS group) or saline (saline group) rectally and CRH mRNA level, plasma ACTH and CORT levels were measured on day 7 after administration of TNBS or saline. In the third experiment, pair‐fed rats whose daily food intake was matched to that of their pair in the colitic group were used, and on day 7 after treatment, CRH mRNA level, plasma ACTH and CORT levels were measured.Results In the first experiment, CRH mRNA levels in the PVN on days 3 and 7 after induction of colitis were significantly lower than those before induction of colitis (P < 0.05, P < 0.01, respectively). Plasma CORT levels during colitis were increased significantly (P < 0.001) from days 1 to 14, and plasma ACTH levels showed no significant change after day 3. In the second experiment, CRH mRNA level in the PVN in the TNBS group was significantly higher than those in the saline group (P < 0.01). In the third experiment, pair feeding resulted in no significant change in CRH mRNA, plasma ACTH and CORT levels.Conclusions These findings indicated that CRH mRNA expression in the PVN was inhibited by glucocorticoid feedback during this experimental colitis, and the decrease in food intake during colitis was not simply responsible for the expression of CRH mRNA.

Towards a unified model of neuroendocrine-immune interaction.

Although the neuroendocrine system has immunomodulating potential, studies examining the relationship between stress, immunity and infection have, until recently, largely been the preserve of behavioural psychologists. Over the last decade, however, immunologists have begun to increasingly appreciate that neuroendocrine-immune interactions hold the key to understanding the complex behaviour of the immune system in vivo. The nervous, endocrine and immune systems communicate bidirectionally via shared messenger molecules variously called neurotransmitters, cytokines or hormones. Their classification as neurotransmitters, cytokines or hormones is more serendipity than a true reflection of their sphere of influence. Rather than these systems being discrete entities we would propose that they constitute, in reality, a single higher-order entity. This paper reviews current knowledge of neuroendocrine-immune interaction and uses the example of T-cell subset differentiation to show the previously under-appreciated importance of neuroendocrine influences in the regulation of immune function and, in particular, Th1/Th2 balance and diurnal variation there of.

Endometrial and myometrial corticotropin-releasing hormone (CRH): its regulation and possible roles

In human endometrium, both epithelial and stroma cells produce corticotropin-releasing hormone (CRH). Both types of cells also possess specific CRH-binding sites indicating a local effect of endometrial CRH. The transcription of the CRH gene in human endometrium is under the control of steroid hormones and locally produced prostanoids and interleukins. Endometrial CRH interacts with locally produced prostaglandins and interleukins. Based on these observations it can be hypothesized that CRH, prostaglandins and interleukins form a network responsible for the communication between epithelial and stromal cells, at the level of the endometrium, and between endometrial and myometrial cells at the level of uterus. The net product of these interaction is the micro-regulation of the decidualizing process and the preparation of endometrium for the implantation/nidation of the conceptus. Indeed, this network may represent the core of the intrauterine neuroendocrine—immune interactions involved in the decidualization of stroma and implantation of blastocyst. In addition, this network appears to be essential for the fine-tuning of myometrial tone.

Neuroendocrine-immune interactions during viral infections

Publisher Summary This chapter discusses the physiological and pathophysiological interplay between the immune and neuroendocrine systems and emphasizes the reciprocal regulation that occurs between endogenous adrenal steroids and cytokines during viral infections. On a fundamental level, the usual consequence of a viral infection is the disruption of the normal physiological equilibrium of the host. Restoration of homeostasis in complex hosts (e.g., mammals) requires that multiple organ systems be coordinated through the action of diffusible mediators, such as cytokines, hormones, and neurotransmitters. Glucocorticoids are immunomodulatory steroid hormones produced by the adrenal cortex under both physiological and pathological conditions. Cortisol is the major endogenous glucocorticoid in humans while corticosterone is its functional equivalent in mice and rats. Interactions between the neuroendocrine and immune systems during viral infection play an important role in immune regulation and maintain a delicate balance between antiviral immune responses and potentially toxic cytokine excesses. Glucocorticoid hormones are induced under the conditions of viral infection and serve to restrain cytokine responses through effects on cytokine gene expression. Consequences of glucocorticoid deficiency during viral infection include increased cytokine messenger RNA and protein and cytokine-mediated toxicity and death.

Neuroendocrine-immune system interactions in amphibians: implications for understanding global amphibian declines.

Amphibians are ancient creatures valued by biologists and naturalists around the world. They share with all other vertebrates a complex neuroendocrine system that enables them to flourish in a variety of aquatic and semiaquatic environments. Studies from a number of laboratories have demonstrated that the immune system of amphibian species is nearly as complex as that of mammals. Yet for reasons that are not well understood, amphibian species are facing greater survival challenges than in the recent past. This article will review our current understanding of the neuroendocrine immune system interactions in amphibians and address the question of whether environmental stressors may contribute to immunosuppression and amphibian declines.

Modulation of the fish immune system by hormones

Immune–neuroendocrine interactions in fish, as in mammals, have become a focus of considerable interest, with the modulation of immune responses by hormones receiving particular attention. Cortisol, growth hormone (GH), prolactin (PRL), reproductive hormones, melanin-concentrating hormone (MCH) and proopiomelanocortin (POMC)-derived peptides have all been shown to influence immune functions in a number of fish species. This review summarises the known effects of these hormones on the fish immune system, as well as the often complex interactions between different hormones. The possible implications for fish health, with respect to aquaculture and the changes in immunocompetence that take place during different stages in the fish life cycle are also discussed.

RECIPROCAL INTERACTIONS BETWEEN THE NEUROENDOCRINE AND IMMUNE SYSTEMS DURING INFLAMMATION

The neuroendocrine and immune responses to inflammatory stress represent important integrated physiologic circuits for the regulation of inflammation whose basis has been reviewed. Proinflammatory cytokines such as IL-1 beta, TNF alpha, and IL-6 released from inflammatory foci initiate a local inflammatory response and travel by way of the blood-stream to the central nervous system, where they trigger a variety of neuroendocrine counterregulatory mechanisms. There is an important NEI loop. Stimulatory signals are received by the neural systems from inflammatory foci and are transduced by the hypothalamus, thereby initiating a complex hormonal and cytokine cascade of reactions aimed at modulating inflammation and returning the organism to normal physiologic homeostasis once the trigger has been neutralized. Conversely, a number of mechanisms that modulate the anti-inflammatory activity of the neuroendocrine responses to inflammation are also activated. Defects in the neuroendocrine-immune interactions can profoundly affect the susceptibility to developing chronic inflammatory disease and influencing survival after bacterial infections. The NEI loop has important pathophysiologic implications for disease processes.

Sexual dimorphism in the hypothalamo-pituitary-adrenal (HPA) axis and TNFalpha responses to phospholipase A2-related neurotoxin (from crotalus durissus terrifcus) challenge.

Neuroendocrine-immune interactions are vital for the individual's survival in certain physiopathological conditions such as sepsis and tissular injury. It is known that several snake venoms (SV) are potent neurotoxic compounds and that their main component is a specific phospholipase type 2 (PLA2). It has been recently described that the venom from crotalus durissus terrificus (SV) possesses a cytotoxic effect in different in vitro and in vivo animal models. In the present study we investigated whether SV is able to stimulate both TNFalpha and neuroendocrine functions in a sexual dimorphic fashion. For this purpose the modulatory role of endogenous sex steroids during neurotoxemia was evaluated. Our results indicate that SV (25 microg/animal) stimulates the hypothalamo-pituitary-adrenal axis and TNFalpha secretion when administered (ip) to adult male mice, such responses were characterized by a time-related enhance in plasma glucose, ACTH, corticosterone and TNFalpha levels. SV-stimulated glycemia, corticosteronemia and adrenal glucocorticoid were sexually dimorphic. Twenty-day gonadectomized mice showed a similar sexual dimorphism to that found in intact animals, however, they additionally showed a sexual dimorphic pattern in cytokine release in plasma 30 min post-SV. Estradiol (E2) treatment, in gonadectomized mice, abolished some characteristics of the sexual dimorphism, such as hyperglycemia, hypercorticosteronemia and hypercytokinemia. Finally, in vitro experiments indicate that: a) gonadectomy increased spontaneous and SV-stimulated cytokine output by incubated peripheral mononuclear cells (PMNC), regardless of the sex; and b) despite E2 treatment, in gonadectomized, did not modify the pattern of basal and SV-elicited TNFalpha secretion induced by orchidectomy, fully reversed the enhance in basal and SV-stimulated cytokine release found after ovariectomy alone. Our results further indicate that neurotoxemia, due to SV challenge, induces several symptoms common to those of inflammatory stress; they also strongly support that both gender and endogenous sex steroids are responsible for neuroendocrine-immunological sexual dimorphism.

Immunological stress in rats induces bodily alterations in saline-treated conspecifics

This work was developed during an investigation on the neuroendocrine–immune interaction in rats immune challenged with sheep red blood cells (SRBC). The structures used for evaluating the immunological response was the direct plaque-forming cells (PFC). An inbred strain of rat was used to overcome the problem of different timings in the peak humoral immune response. Normal rats were injected intraperitoneally with saline or SRBC and were killed 0, 3, 4, 5, and 6 days later. Body and gland weights were recorded, and.serum levels of corticosterone and prolactin were quantified by radioimmunoassay. The hormone levels and gland weights of the saline conspecifics and SRBC-treated rats were found to be similar. When new rats were housed in a separate room and treated with physiological saline, there were again no differences in the body and gland weights or the serum hormone levels between the two home cage control (HCC) groups of animals. Compared with saline conspecifics and SRBC-treated groups, the HCC groups had higher body weights from the third to the sixth day of treatment and had lower gland weights in absolute and relative analysis (pituitary, thyroid, and adrenals) mainly on the fourth and fifth days; thymus weights were highest on the third day. Corticosterone and prolactin levels were significantly lower on the fifth and sixth days, respectively. Because SRBC-treated rats showed a peak direct immune response on the fourth and fifth days and showed peak corticosterone levels on the fifth day after treatment, we conclude that the former animals were under stress and influenced their saline conspecifics through sound or smell. This conclusion agrees with other studies, showing that physically or emotionally stressed rats can influence conspecifics through noise and body odors.

Focal adhesion kinases: interest in immunoendocrinology, developmental biology, and cancer.

The research field on focal adhesion-related kinases started a decade ago, but the term focal adhesion was introduced for the first time nearly 20 yr before. Since its identification, many studies have enlightened the role of the first intermediate of focal adhesion-related signals in a large number of biologic and physiologic processes. In this review, we try to integrate the most recent data about the known focal adhesion-related kinases, and we focus on three topics in which they deserve great interest: neuroendocrine-immune interactions, developmental biology, and proliferative diseases.

Individual Behavioral Characteristics of Wild-Type Rats Predict Susceptibility to Experimental Autoimmune Encephalomyelitis

Neuroendocrine–immune interactions are thought to be important in determining susceptibility to autoimmune disease. Animal studies have revealed that differences in susceptibility to experimental autoimmune encephalomyelitis (EAE) are related to reactivity in the hypothalamo–pituitary–adrenal axis. It is known that there is a close relation between neuroendocrine parameters and behavioral characteristics, suggesting that behavior and disease susceptibility may be associated. In the present study we investigated whether behavioral characteristics of wild-type rats are related to susceptibility to disease. We show here that the latency of the animal to attack an intruder correlates significantly with the EAE disease score: animals that do not attack the intruder during the test period are more resistant to the disease than animals with short attack latency times. These data, obtained in an unselected strain of wild-type rats, demonstrate that behavioral response patterns of individual animals can in part predict susceptibility to autoimmune disease.

Generation of a Recombinant Herpes Simplex Virus Type 1 Expressing the Rat Corticotropin- Releasing Hormone Precursor: Endoproteolytic Processing, Intracellular Targeting and Biological Activity

We describe the generation of a recombinant herpes simplex virus type 1 (HSV1) vector, tsK/CRH10, derived from the temperature-sensitive mutant tsK, expressing rat pre-procorticotropin-releasing hormone (ppCRH). In hypothalamic neurons, within the paraventricular and supraoptic nuclei, this neuropeptide precursor is processed to mature CRH (1–41), the key modulator of the hypothalamic-pituitary-adrenal stress response. We used the recombinant HSV1 tsK/CRH10 to study posttranslational processing, intracellular localization and biological activity of proCRH (pCRH) within neuronal, glial and epithelial cell lines. We showed that CRH-like immunoreactivity expressed in neuronal, glial and epithelial cells infected with tsK/CRH10 was biologically active, could be detected intracellularly and was also secreted. Our data also show that within Neuro2a and NG115 cells, the CRH precursor is cleaved to yield a CRH-like immunoreactive fragment of approximately 4.75 kD which could account for mature CRH (1–41). No endoproteolytic processing of the precursor takes place within the astrocytic 1321 NI cell line. Using immunocytochemistry techniques we detected CRH-like immunoreactivity within the endoplasmic reticulum-Golgi region in all cells and within secretory vesicles of Neuro2a and NG115 cells, suggesting correct targeting to the regulated secretory pathway within these cells. Our results demonstrate that the HSV1 recombinant vector expressing the full-length CRH precursor molecule constitutes an excellent delivery system for both cell lines and postmitotic neurons in vitro, which has enabled the study of targeting, endoproteolytic processing and biological activity of this neuropeptide precursor. Furthermore, it can also be used to generate transient transgenesis of the CRH precursor in vivo, to study neuroendocrine-immune interactions within the mammalian central nervous system.