bluuebunny/crossref_metadata_2025 huggingface dataset:
Melatonin Rhythms in Mice: Role in Autoimmune and Lymphoproliferative Diseases
Authors: CONTI ARIO , MAESTRONI GEORGES J. M.
Published: February 2006

Abstract: Production of melatonin (MLT) in the pineal gland (PG) of inbred mice such as C57BI/6J, BALB/c, and AKR strains is still a matter of debate. In a recent study we validated the presence of MLT in the PG of these inbred mice. We found a short‐term MLT peak in the middle of the dark period with a pattern that mirrors that found previously in the serum. In another study, based on the known immunoregulatory role of MLT, we investigated the role of the PG and MLT in autoimmune diabetes mellitus type I using, as an experimental model, female nonobese diabetic (NOD) mice. Mice were pinealectomized or treated chronically with MLT (injected subcutaneously or administered via drinking water). We found that neonatal pinealectomy accelerates the development of disease in female NOD mice, whereas exogenous MLT protects animals. This is in spite of the fact that MLT increased the production of insulin autoantibodies (IAA). We conclude that PG and MLT influence the development of autoimmune diabetes, although the mechanism of action needs further investigation.
κ‐Opioid Receptors in Marrow Stroma Mediate the Hematopoietic Effects of Melatonin‐Induced Opioid Cytokinesaa
Authors: MAESTRONI GEORGES J. M.
Published: February 2006

Abstract: Melatonin exerts colony‐stimulating activity and rescues myeloid progenitors from apoptosis, induced either in vivo or in vitro by cancer chemotherapy compounds in tumor‐bearing mice. These effects are mediated mainly by T‐helper cell‐derived opioid cytokines with an apparent molecular mass of 15 kDa and 67 kDa that are recognized both by anti‐interleukin‐4 and anti‐dynorphin B antibodies. These putative new cytokines were named melatonin‐induced‐opioid (MIO). The most active and naltrexone‐sensitive MIO was the smaller molecule, which was called MIO15 and found to act on an opioid‐binding site present in adherent bone marrow cells. However, the hematopoietic action of MIO15 was dependent on the presence of colony‐stimulating factors (CSF). To investigate this point, we studied the ability of melatonin to rescue granulocyte/macrophage colony‐forming units (GM‐CFU) in the bone marrow of tumor‐free animals treated with cancer chemotherapeutic compounds. We found that melatonin not only is unable to protect bone marrow GM‐CFU unless the mice are transplanted with Lewis lung carcinoma (LLC), but also that melatonin seems to increase the myelotoxicity of cyclophosphamide in tumor‐free mice. In both tumor‐bearing or healthy mice, the effect of melatonin is negated by naltrexone, indicating the involvement of MIO15. Competition studies classified the target opioid‐binding site as a κ‐opioid receptor with low affinity in tumor‐free mice and high affinity in LLC‐implanted mice. LLC is known to release CSF. Consistently, addition of CSF in the form of lung‐conditioned medium (LCM) to adherent bone marrow cells increased the affinity of the κ‐opioid receptor. Addition of anti‐granulocyte/macrophage colony‐stimulating factor (GM‐CSF) mAbs neutralized the effect of LCM. In conclusion, the affinity state of the k‐opioid receptors in stromal bone marrow cells seems to modulate the hematopoietic effect of melatonin and/or MIO15.
Altered Neuroimmunoendocrine Communication during a Condition of Chronically Increased Brain Corticotropin‐Releasing Hormone Drivea
Authors: REUL JOHANNES M. H. M. , LABEUR MARTA S. , WIEGERS G. JAN , LINTHORST ASTRID C. E.
Published: February 2006

Abstract: Presently, it is clear that the brain, immune system, and endocrine system build a complex network of interactions at various levels. Inflammation, which may be regarded as a stressful challenge, initiates apart from immunological, autonomic, and neuroendocrine responses also profound behavioral (e.g., immobility, social disinterest) changes. Key mediators herein are corticotropin‐releasing hormone (CRH) and cytokines, such as interleukin‐1β (IL‐1β). Currently, the behavioral changes, collectively termed sickness behavior, are thought to be adaptive responses to support the body's efforts to fight the infection. Using in vivo microdialysis and biotelemetry in freely moving animals, we have studied the monoaminergic circuits in the brain implicated in the regulation of physiological and behavioral responses to a peripheral inflammatory challenge (see also chapter of Linthorst and Reul in this volume). To expand our insight into the relationship between hypersecretion of CRH and physiological and behavioral abnormalities associated with stress‐related disorders, a series of experiments was conducted with long‐term centrally CRH‐infused rats. These rats showed reduced body weight gain, decreased food intake, elevated plasma ACTH and corticosterone levels, thymus involution and immunosuppression, but, paradoxically, enhanced IL‐1β mRNA expression in spleen macrophages. After a peripheral endotoxic challenge on the seventh day of treatment, the CRH‐infused rats produced aberrant (i.e., blunted and/or delayed) HPA axis, fever, behavioral, and hippocampal serotonergic responses. However, endotoxin‐induced plasma IL‐1 and IL‐6 bioactivities were significantly enhanced in these animals. The data show that chronically elevated central CRH levels as occurring during chronic stress result in defective central nervous system and immune system responses to an acute (inflammatory) challenge. These observations provide evidence that chronic CRH hypersecretion is an important factor in the etiology of stress‐related disorders.
A Novel Endogenous Corticotropin Release Inhibiting Factor
Authors: REDEI EVA , RITTENHOUSE PETER A. , REVSKOY SERGEI , McGIVERN ROBERT F. , AIRD FRASER
Published: February 2006

Abstract:ACTH is the major regulator of the body's adaptive response to stress and the physiological stimulus for glucocorticoid secretion. A hypothalamic corticotropin release inhibiting factor (CRIF) that inhibits ACTH synthesis and secretion has long been postulated but was not characterized until recently. We have recently identified a 22 amino acid peptide, prepro‐thyrotropin releasing hormone (TRH) 178‐199 that inhibits basal and stimulated ACTH synthesis and secretionin vitroand stress‐induced ACTH secretionin vivo. Prepro‐TRH 178‐199 is abundant in several brain regions, including the external zone of the median eminence, where its concentration changes in response to stress. We propose that this peptide is a physiological regulator of ACTH production: an endogenous CRIF. Because prepro‐TRH 178‐199 is encoded within the same precursor as TRH, its expression is likely to be negatively regulated by thyroid hormones leading to changes in endogenous glucocorticoid levels. Streptococcal cell wall (SCW)‐induced inflammation, a model of rheumatoid arthritis (RA), was alleviated after long‐term thyroxine treatment. Inversely, a hypothyroid milieu led to decreased basal hypothalamic‐pituitary‐adrenal activity, but increased expression of IL‐1β and MIP‐1α, specific markers for RA in humans. These results suggest that this putative CRIF may be an important component in the development of RA and that regulation of preproTRH may be highly relevant to the development of other autoimmune diseases that are also exacerbated by low endogenous glucocorticoid levels.
Neuroendocrine Control of the Thymusa
Authors: SAVINO WILSON , VILLA‐VERDE DÉA MARIA SERRA , ALVES LUIZ ANASTACIO , DARDENNE MIREILLE
Published: February 2006

Abstract: Thymocytes undergo a complex process of differentiation, largely dependent on interactions with the thymic microenvironment, a tridimensional cellular network formed by epithelial cells, macrophages, dendritic cells, and fibroblasts. One key cellular interaction involves the TCR‐CD3 complex expressed by thymocytes with MHC‐peptide complexes present on microenvironmental cells. Additionally, thymic epithelial cells (TEC) interact with thymocytes via soluble polypeptides such as thymic hormones and interleukins, as well as through extracellular matrix (ECM) ligands and receptors. Such types of heterotypic interactions are under neuroendocrine control. For example, thymic endocrine function, represented by thymulin production, is up‐regulated, both in vivo and in vitro, by thyroid and pituitary hormones, including prolactin and growth hormone. We also showed that these peptides enhance the expression of ECM ligands and receptors, as well as the degree of TEC‐thymocyte adhesion. In addition, we studied the thymic nurse cell complex, used herein as an in vitro model for ECM‐mediated intrathymic T‐cell migration. We observed that T‐cell migration is also hormonally regulated as ascertained by the thymocyte entrance into and exit from these lymphoepithelial complexes. Taken together these data clearly illustrate the concept that neuroendocrine circuits exert a pleiotropic control on thymus physiology. Lastly, the intrathymic production of classic hormones such as prolactin and growth hormone suggests that, in addition to endocrine circuits, paracrine and autocrine interactions mediated by these peptides and their respective receptors may exist in the thymus, thus influencing both lymphoid and microenvironmental compartments of the organ.
The Hypothalamo‐Pituitary‐Adrenal Axis of Athymic Swiss Nude Mice: The Implications of T Lymphocytes in the ACTH Release from Immune Cellsa
Authors: GAILLARD R. C. , DANEVA T. , HADID R. , MULLER K. , SPINEDI E.
Published: February 2006

Abstract: Because of the well‐known role of the thymus in the regulation of immune function, we investigated whether the lack of thymus may affect hypothalamo‐pituitary‐adrenal (HPA) axis activity. Eight‐week‐old female Swiss nude (athymic) and BALB/c (normal) mice were used to study (a) the “in vivo” response of the HPA axis to various stresses and stimuli acting at either hypothalamic, pituitary, or adrenal levels and (b) the in vitro response of pituitary and adrenal cells to CRH and ACTH stimulation, respectively. The results indicate that (1) basal plasma ACTH levels were significantly (p < 0.05) higher in Swiss nude than in BALB/c mice, whereas basal corticosterone (B) levels were similar in both strains of mice; (2) the stress‐induced release of ACTH and B in plasma was significantly (p < 0.05) lower in Swiss nude than in BALB/c mice, regardless of the stimulus applied; (3) the “in vitro” pituitary response to CRH and the adrenal response to ACTH were significantly (p < 0.05) lower in Swiss nude than in BALB/c mice; and (4) whereas hypothalamic CRH and pituitary ACTH contents were similar in both strains, adrenal B content was significantly (p < 0.05) lower in athymic mice. Immune reconstitution of the athymic nude mice by injecting splenocytes obtained from syngeneic heterozygous (i.e., immunologically fully competent) donors produced a significant increase in the B adrenal content of the nude mice. Among the splenocytes, CD4+ T‐lymphocytes play a particularly important role in the release of ACTH from cells of the immune system. In conclusion, our results indicate that athymic nude mice have a blunted HPA axis response to various stresses and stimuli; this defect seems to reside at both the pituitary and adrenal levels. Immune reconstitution of the nude mice leads to a normalization of the adrenal B content.
Neuroimmunomodulation of Aging: A Program in the Pineal Gland
Authors: PIERPAOLI WALTER
Published: February 2006

Abstract: We have investigated for 35 years the relationship between the neuroendocrine and the thymo‐lymphatic, immune system. In the last decade we have shown that the pineal gland is a main adapter and fine synchronizer of environmental variables and endogenous messages into physiological modifications of basic functions. In particular the pineal gland itself seems to regulate, via circadian, night secretion of melatonin, all basic hormonal functions and also immunity. We have shown with several in vivo models that this fundamental role of the pineal gland decays during aging. Aging itself seems to be a strictly pineal‐programmed event similar to growth and puberty. The continuation of our interventions with melatonin against the typical degenerative diseases of aging must be based on an accurate evaluation of its mechanisms of action. Melatonin being a ubiquitous molecule in nature, we suggest that it has acquired during evolution of the species numerous levels of activities. In fact, melatonin can be found in a large variety of cells and tissues, and bindings sites and “receptors” have been identified in many tissues and cells of the neuroendocrine and immune system. Therefore, the progressive understanding of the aging‐programing role of the pineal gland also depends on studies of melatonin and its basic regulatory function. Our present studies will be described.
Prolactin: A Hormone at the Crossroads of Neuroimmunoendocrinology
Authors: GOFFIN VINCENT , BOUCHARD BRIGITTE , ORMANDY CHRISTOPHER J. , WEIMANN EDDA , FERRAG FATIMA , TOURAINE PHILIPPE , BOLE‐FEYSOT CHRISTINE , MAASKANT RONDA A. , CLEMENT‐LACROIX PHILIPPE , EDERY MARC , BINART NADINE , KELLY PAUL A.
Published: February 2006

Abstract: Prolactin (PRL), secreted by the pituitary, decidua, and lymphoid cells, has been shown to have a regulatory role in reproduction, immune function, and cell growth in mammals. The effects of PRL are mediated by a membrane‐bound receptor that is a member of the superfamily of cytokine receptors. Formation of a trimer, consisting of one molecule of ligand and two molecules of receptor, appears to be a necessary prerequisite for biological activity. The function of these receptors is mediated, at least in part, by two families of signaling molecules: Janus tyrosine kinases (JAKs) and signal transducers and activators of transcription (STATs). To study these receptors, we have used two approaches: mutational analysis of their cytoplasmic domains coupled with functional tests and inactivation (knockout) of the receptor gene by homologous recombination in mice. We have produced mice by gene targeting in embryonic stem cells carrying a germline null mutation of the prolactin receptor gene. Heterozygous (+/‐) females show almost complete failure to lactate, following their first, but not subsequent pregnancies. Homozygous (‐/‐) females are infertile as a result of multiple reproductive abnormalities, including ovulation of premiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Half of the homozygous males are infertile or show reduced fertility. In view of the widespread distribution of PRL receptors, other phenotypes including those on the immune system, are currently being evaluated in ‐/‐ animals. This study establishes the prolactin receptor as a key regulator of mammalian reproduction and provides the first total ablation model to further study the role of the prolactin receptor and its ligands.
Insulin Growth Factor‐I Inhibits Apoptosis in Hematopoietic: Progenitor Cells Implications in Thymic Aginga
Authors: KELLEY KEITH W. , MEIER WILLIAM A. , MINSHALL CHRISTIAN , SCHACHER DANIEL H. , LIU QIANG , VANHOY ROGER , BURGESS WILLIAM , DANTZER ROBERT
Published: February 2006

Abstract: A decline in plasma concentrations of both growth hormone and IGF‐I occurs during aging of humans and rodents, and this is accompanied by involution of the thymus gland. Exogenous growth hormone induces the synthesis of IGF‐I, which acts on bone marrow‐derived hematopoietic progenitors of the myeloid and lymphoid lineages to promote their replication and survival. The increase in survival of these cells is caused by the ability of IGF‐I to inhibit their apopotic death. In contrast to the multipotential colony‐stimulating‐factor IL‐3, inhibition of apoptosis by IGF‐I requires the activation of the critical intracellular effector PI 3‐kinase. These data establish that hematopoietic progenitors can use more than one intracellular signaling pathway in order to maintain their survival. The data also extend the original hypothesis 48 that IGF‐I shares with the colony‐stimulating factors the properties of promoting DNA synthesis and inhibiting programmed cell death. Collectively, these data establish that hematopoietic progenitor cells are important targets for IGF‐I, and this is likely to be important in understanding thymic aging.
The Substance P and Somatostatin Interferon‐γ Immunoregulatory Circuita
Authors: WEINSTOCK JOEL V. , ELLIOTT DAVID
Published: February 2006

Abstract: Murine schistosomiasis mansoni is a parasitic disease in which flukes living in the portal vein of the host produce ova that deposit in the liver and intestines. In these organs, ova release antigens that induce chronic, focal granulomatous inflammation. IFN‐γ is an inflammatory cytokine important in macrophage activation and B‐cell differentiation. A substance P (SP)/somatostatin (SOM) neurokine immunoregulatory circuit controls IFN‐γ production in schistosome granulomas. SP stimulates, while SOM inhibits IFN‐γ release, modulating IFN‐γ‐dependent circuitry. SP and SOM function through interaction with authentic SP and SOM receptors located on granuloma T cells. Also, the granulomas produce authentic SP and SOM14, as evidenced by the presence of mRNA and product. The granulomas have no nerves. This and other data suggest that the inflammatory cells make these neurokines. Granuloma macrophages produce SOM. Macrophages from various sources express SOM mRNA in response to LPS, IFN‐γ, IL‐10 or several other inflammatory mediators. Thus, the inflammation of murine schistosomiasis has a complete SP/SOM immunoregulatory circuit, which in turn is subject to immunoregulation.
Selective Regulation of T‐Cell Development and Function by Calcitonin Gene‐Related Peptide in Thymus and Spleen: An Example of Differential Regional Regulation of Immunity by the Neuroendocrine Systema
Authors: BULLOCH K. , McEWEN B. S. , NORDBERG J. , DIWA A. , BAIRD S.
Published: February 2006

Abstract: In the course of our studies, we have shown the presence of calcitonin gene related peptide (CGRP) by immunocytochemistry in cell bodies and nerve fibers of the murine thymus and in a sparce innervation of the spleen. Receptors for CGRP have been characterized within these glands, and their activation by physiological levels of CGRP was found to suppress Con A‐stimulated proliferation of thymocytes and splenic T cells as well as antigen‐specific T‐cell proliferation. This suppression is blocked by the antagonist for CGRP (CGRP 8‐37). Within the thymus cultures, the antagonist CGRP (8‐37) alone enhanced proliferation of thymocytes during Con A stimulation, most likely by inhibiting the endogenous release of CGRP into the culture medium by resident thymocytes. Some of the CGRP‐induced suppression of mitogenic stimulation of thymocytes, but not of splenocytes, was due to apoptosis. The antagonist, CGRP(8‐37), did not block apoptosis caused by Con A or CGRP but rather enhanced it. Flow cytometric analysis of CGRP‐treated cultures using antibodies to cluster determinates (CD) showed that the majority of thymocytes undergoing apoptosis induced by CGRP were of the CD4/CD8 double‐positive type. These data indicate that apoptosis in the thymocytes is mediated by a CGRP receptor not sensitive to the antagonist CGRP(8‐37). Because proliferation of thymocytes and splenocytes induced by Con A is blocked by this antagonist and splenocytes are refractory to CGRP induced apoptosis, CGRP appears to mediate at least two separate functions on subpopulations of thymocytes and T cells via two different CGRP receptors within the gland. These effects of a neuropeptide exemplify the phenomenon of differential regional regulation of immunity by the autonomic and neuroendocrine systems.
Levels of Analysis in Health Science: A Framework for Integrating Sociobehavioral and Biomedical Research
Authors: ANDERSON NORMAN B.
Published: February 2006

Abstract: One of the principal goals of the Office of Behavioral and Social Sciences Research at the National Institutes of Health is to facilitate interdisciplinary research between social, behavioral, and biomedical scientists. The purpose of this paper is to provide a framework for such interdisciplinary health research. The essence of this framework is the concept of levels of analysis in the health sciences. These levels include the social/environment, behavioral/psychological, organ systems, cellular, and molecular. The interdependence of these five levels of analysis suggests that advances in the health sciences may be accelerated by a more integrated, multilevel approach to research. The principles of integrated, multilevel research are outlined, and examples of research that support this approach are presented. Finally, some of the activities of the Office of Behavioral and Social Sciences Research that will further interdisciplinary research across levels of analysis are summarized.
Neuroendocrine‐Immune Disturbances in Animal Models with Spontaneous Autoimmune Diseasesa
Authors: WICK GEORG , SGONC ROSWITHA , LECHNER OSKAR
Published: February 2006

Abstract: According to our concept, the development of autoimmune diseases depends on the presence of two sets of essential genes, one coding for an abnormal autoreactivity of the immune system, the other for a primary susceptibility of the target organ/structure for the immune attack. The final outcome of the disease in a given individual is then fine tuned by modulatory factors, such as diet or hormones. With regard to the latter, the immuno‐endocrine interaction via the hypothalamo‐pituitary‐adrenal (HPA) axis has proven to be of special importance. Investigating the so‐called Obese strain (OS) of chickens, an animal model with a spontaneously occurring Hashimoto‐like autoimmune thyroiditis, we have first shown an impaired surge of glucocorticoid hormones after stimulation of the HPA axis by antigens or certain cytokines (glucocorticoid‐increasing factors‐GIFs). More recently, we have found a similar behavior in models with systemic autoimmune diseases, that is, murine lupus erythematosus and avian scleroderma. More detailed studies have, however, proven that the mechanisms underlying this altered immuno‐endocrine communication via the HPA axis differs in different models. Finally, recent data point to the possibility that the classical pathways of glucocorticoid‐T‐cell interactions also take place in the thymus itself, which has been shown to be a site of steroid hormone production.
Cytokines and Fevera
Authors: BLATTEIS CLARK M. , SEHIC ELMIR
Published: February 2006

Abstract: Fever is induced in response to the entrance of pathogenic microorganisms into the body and is thought to be mediated by cytokines. Because these pathogens most commonly invade the body through its natural barriers and because body temperature is regulated centrally, these mediators are presumed to be produced peripherally and transported by the bloodstream to the brain, to act. It is generally considered that their febrigenic messages are further modulated there by prostaglandin E2 (PGE2). However, the detailed mechanism by which these cytokines signal the brain and activate the febrile response is not yet clear. Indeed, the specific role of each cytokine has been difficult to establish due to complex interactions among them. Furthermore, recent evidence suggests that different pyrogens may induce different cytokines; for example, i.v. LPS (a model of systemic bacterial infection) induces large increases in IL‐6, but only small rises in IL‐1 and TNFα plasma levels. Moreover, their appearance lags the fever onset. We recently found that subdiaphragmatic vagotomy, decomplementation, and blockade of Kupffer cells suppress the febrile response of guinea pigs to i.v. LPS, and that i.v. LPS rapidly stimulates the release of norepinephrine (NE) and, hence, of PGE2 in their preoptic‐anterior hypothalamus (POA, the brain region containing the thermoregulatory controller). Based on these and other data in the literature, we hypothesize that LPS fever may be initiated as follows: i.v., LPS → complement → Kupffer cells → cytokines?→ vagal afferents → n. tractus solitarius?→ A1/A2 cell groups?→ ventral noradrenergic bundle?→ POA → NE → PGE2→ fever.
Neuroimmune Mechanisms of Intestinal Responses to Stress: Role of Corticotropin‐Releasing Factor and Neurotensin
Authors: POTHOULAKIS CHARALABOS , CASTAGLIUOLO IGNAZIO , LEEMAN SUSAN E.
Published: February 2006

Abstract: Previous studies showed that exposure of experimental animals to immobilization stress increases colonic motility and that these effects are mediated by release of corticotropin‐releasing factor (CRF). Studies from our laboratory showed that 30‐min immobilization stress of rats caused several not previously described colonic responses to stress, including increased colonic mucin and prostaglandin E2 (PGE2) secretion, increased colonic mucosal levels of cyclooxygenase‐2 (COX‐2) mRNA, and degranulation of colonic mast cells. These stress‐associated colonic changes were reproduced by intravenous or intracerebral injection of CRF in conscious, nonstressed rats. Furthermore, pretreatment of rats with the CRF antagonist α‐helical CRF9‐41, hexamethonium, or the mast cell stabilizer lodoxamide inhibited our observed colon responses to immobilization stress. Our results indicate that CRF released during immobilization stress increases colonic transit via a neuronal pathway and stimulates colonic mucin release via activation of neurons and colonic mast cells. These results provide support for an important role for CRF in stress‐mediated colonic responses and a link between the nervous and the immune systems.
The Influence of Psychological Stress on the Immune Response to Vaccinesa
Authors: GLASER RONALD , KIECOLT‐GLASER JANICE K. , MALARKEY WILLIAM B. , SHERIDAN JOHN F.
Published: February 2006

Abstract: We compared virus‐specific antibody and T‐cell responses to influenza virus vaccination in 32 caregivers of Alzheimer's disease (AD) patients and matched control subjects. Caregivers showed a poorer antibody response and virus‐specific T‐cell response following vaccination compared to the control subjects as measured by fourfold increases in antibody titers to the vaccine and lower levels of virus‐induced IL‐2 levels in vitro. We performed a second study in which forty‐eight medical students were inoculated with a series of three injections of the hepatitis‐B (HEP‐B) vaccine to coincide with the third day of three, three‐day examination blocks. Twelve of the 48 medical students seroconverted after the first injection; these students were characterized by falling into the lower stressed/lower anxiety group of students. Students who reported greater social support and lower anxiety and stress demonstrated a higher antibody response to the vaccine and a more vigorous T‐cell response to HEP‐B surface antigen at the end of the third examination experience. The differences in antibody and T‐cell responses to HEP‐B and influenza virus vaccinations provide a demonstration of how stress may be able to alter both the cellular and humoral immune responses to vaccines and novel pathogens in both younger and older adults.
Marital Stress: Immunologic, Neuroendocrine, and Autonomic Correlatesa
Authors: KIECOLT‐GLASER JANICE K. , GLASER RONALD , CACIOPPO JOHN T. , MALARKEY WILLIAM B.
Published: February 2006

Abstract: Ninety newlywed couples (mean age = 25), selected on the basis of extremely stringent mental and physical health criteria, were admitted to a hospital research unit for 24 hours to provide a detailed assessment of conflict‐resolution behaviors and changes in autonomic, endocrine, and immune function. Among these newlyweds, negative or hostile behaviors during marital conflict (coded from videotaped interactions) were associated with increased levels of epinephrine, norepinephrine, growth hormone, and ACTH as well as greater immunological change over the subsequent 24 hours. Wives demonstrated greater and more persistent physiological changes related to marital conflict than husbands. To assess the generalizability of these physiological changes, a similar laboratory paradigm was used with 31 older couples (mean age = 67) who had been married an average of 42 years. Consistent with the data from newlyweds, both endocrinological and immunological data showed significant relationships to negative behavior during marital conflict in these older couples. These findings suggest that abrasive marital interactions have important endocrinological and immunological correlates.
Evidence for and Pathophysiologic Implications of Hypothalamic‐Pituitary‐Adrenal Axis Dysregulation in Fibromyalgia and Chronic Fatigue Syndrome
Authors: DEMITRACK MARK A. , CROFFORD LESLIE J.
Published: February 2006

Abstract: Chronic fatigue syndrome (CFS) is characterized by profound fatigue anad an array of diffuse somatic symptoms. Our group has established that impaired activation of the hypothalamic‐pituitary‐adrenal (HPA) axis is an essential neuroendocrine feature of this condition. The relevance of this finding to the pathophysiology of CFS is supported by the observation that the onset and course of this illness is excerbated by physical and emotional stressors. It is also notable that this HPA dysregulation differs from that seen in melancholic depression, but shares features with other clinical syndromes (e.g., fibromyalgia). How the HPA axis dysfunction develops is unclear, though recent work suggests disturbances in serotonergic neurotransmission and alterations in the activity of AVP, an important co‐secretagogue that, along with CRH, influences HPA axis function. In order to provide a more refined view of the nature of the HPA dusturbance in patients with CFS, we have studied the detailed, pulsatile characteristics of the HPA axis in a group of patients meeting the 1994 CDC case criteria for CFS. Results of that work are consistent with the view that patients with CFS have a reduction of HPA axis activity due, in part, to impaired central nervous system drive. These observations provide an important clue to the development of more effective treatment to this disabling condition.
The Reactivity of the Cardiovascular System and Immunomodulation by Catecholamines in Juvenile Chronic Arthritis
Authors: KAVELAARS ANNEMIEKE , de JONG‐de VOS van STEENWIJK TEAU , KUIS WIETSE , HEIJNEN COBI J.
Published: February 2006

Abstract: Juvenile chronic arthritis is associated with clinical symptoms indicating that there is a dysregulation of the sympathetic nervous system (SNS). Our data show that patients with juvenile chronic arthritis have an altered function of the SNS associated with increased central noradrenergic outflow, presumably leading to increased vasoconstriction, resulting in a decreased response to an orthostatic stressor. We also investigated the consequences of the altered reactivity of SNS for the reactivity of the immune system to mediators of the sympathetic nervous system and to glucocorticoids. It appeared that leukocytes of these patients have an altered response to catecholamines. Triggering of the β2‐adrenergic receptor leads to reduced cAMP responses that are due to the higher rate of cAMP degradation. In addition, catecholamines induce the production of IL‐6 by leukocytes of these patients, via triggering of α1‐adrenergic receptors. Healthy controls do not express functional α1‐adrenergic receptors.
Neuroendocrine Influences on Experimental Autoimmune Encephalomyelitis
Authors: WHITACRE CAROLINE C. , DOWDELL KENNICHI , GRIFFIN ANN C.
Published: February 2006

Abstract: Experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis, is an inflammatory disease of the CNS mediated by autoreactive T lymphocytes directed against the neuroantigen, myelin basic protein (MBP). EAE is inducible in the Lewis rat, which exhibits an acute monophasic disease, and in selected mouse strains, which show a remitting‐relapsing or chronic course of paralysis. We examined the effects of neuroendocrine modulation by restraint stress on these models of EAE. In Lewis rats, daily cycles of restraint resulted in significant suppression of both clinical and histopathologic changes of EAE. Suppression of EAE was more pronounced in the female than in the male rat, which follows from the higher endogenous corticosterone levels in the female. Mechanistic studies suggested that stress affected the processing of MBP or the T‐cell idiotype. In the relapsing murine model of EAE, B10.PL mice were restrained beginning either before MBP challenge or after the establishment of relapsing disease. We observed a striking inhibition of EAE clinical signs in mice stressed before challenge relative to nonstressed controls. Interestingly, approximately 10 days after termination of the stress period, clinical signs returned and were as severe or more severe than in control nonstressed animals. Stress administered after relapsing EAE was established had no protective effect. In vitro parameters revealed that only stress initiated before disease induction significantly reduced the frequency of MBP‐specific lymphocytes in the spleen and lymph nodes. Both Th1 and Th2 cytokine responses were suppressed in stressed mice. T‐cell receptor transgenic mice exposed to restraint showed a marked decreased in the number and functional activity of transgene‐positive lymphocytes. In summary, elevated levels of endogenous neuroendocrine hormones exert a profoundly suppressive effect on both acute and chronic models of autoimmune CNS injury.
Pathophysiologic and Somatic Investigations of Hypothalamic‐Pituitary‐Adrenal Axis Activation in Patients with Depression
Authors: MICHELSON DAVID , GOLD PHILIP W.
Published: February 2006

Abstract: Preclinical studies of inflammatory and autoimmune illnesses have demonstrated the importance of central components of the HPA axis in disease pathophysiology. The implications of these data for human illness are poorly understood. We have studied the pathophysiology of the hypercortisolism seen in two human illnesses involving the central nervous system, multiple sclerosis (MS) and depression, and looked for demonstrable somatic changes that may be associated with such hypercortisolism. Data from a study of medication‐free patients with multiple sclerosis not in acute exacerbation suggest that compared with depression, MS is associated with increased prominence of hypothalamic vasopressin secretion (p < 0.05). Data from studies of depressed patients with mild to moderate hypercortisolism (assessed by 24‐hour urinary free cortisol excretion) demonstrate marked reductions in bone mineral density compared to healthy, carefully matched controls (p < 0.001), as well as changes in markers of bone metabolic activity similar to those seen in patients with Cushing's disease or exogenous glucocorticoid treatment (p < 0.05). Taken together, these studies suggest HPA axis dysregulations demonstrated in preclinical models of autoimmune and inflammatory illness also occur in human illness and may have important and lasting somatic sequelae.
Neuroimmunomodulation in Inflammatory Bowel Disease: How Far from “Bench” to “Bedside”?a
Authors: ANTON PETER A. , SHANAHAN FERGUS
Published: February 2006

Abstract: The chronic inflammatory bowel diseases (BID), Crohn's disease and ulcerative colitis, are characterized by recurrent periods of inflammation and tissue destruction. The clinical course is influenced by genetics, environmental factors, and the immune system. Recent insights (bench trials) benefiting from advances in genetic engineering and molecular biology have contributed to clinical care (bedside) in terms of actual or potential therapies. Does the neuroendocrine system significantly modify disease activity? Although conceptually appealing, evidence remains circumstantial. Compelling anecdotal reports exist that “stress” affects disease activity in terms of the frequency and severity of IBD flares (bedside), but the mechanisms underlying these observations are unknown. Evidence that neuroendocrine factors play a significant role in immunomodulation is progressing (bench). (i) Trinitrobenzene sulfonic acid (TNB)‐induced colitis, although similar in unstressed Fisher and Lewis rats, shows marked worsening in stressed Lewis rats. (ii) Early studies of rectal pain perception suggest there are specific differences in neuroimaging studies (PET scans) in IBD patients compared to controls. (iii) Levels of substance P (SP) and its receptor are altered. (iv) Preliminary clinical studies with SP receptor antagonists show a trend toward improvement. (v) Importantly, the placebo response in clinical trials is as high as 45%. Evidence that neuroendocrine systems significantly modulate local inflammation is rapidly accumulating (bench), which will facilitate enhanced coordination of clinically relevant therapies (bedside).
Mechanisms of Glucocorticoid‐Resistant Asthmaa
Authors: LEUNG DONALD Y. M. , de CASTRO MARGARET , SZEFLER STANLEY J. , CHROUSOS GEORGE P.
Published: February 2006

Abstract: The term “steroid‐ or glucocorticoid‐resistant (GR) asthma” has been used to describe a group of asthmatics who demonstrate persistent airway obstruction and inflammation despite treatment with high doses of systemic glucocorticoids (GCs). There are at least two forms of GR asthma. The first group of patients has an acquired form of GC resistance. Analysis of their bronchoalveolar lavage (BAL) cells indicates an extremely high level of IL‐2 and IL‐4 gene expression as compared to BAL cells from GC‐sensitive asthmatics. The incubation of T cells from normal individuals with the combination of IL‐2 and IL‐4 induces GC receptor binding defects, and concomitant GC receptor β expression, in their cells. Similar abnormalities in GC receptor binding defects can be detected in freshly isolated cells from type 1 GR asthmatics, but this defect is reversible when their cells are cultured in the absence of IL‐2 and IL‐4. The second group involves patients with primary GC resistance who do not develop side effects on high‐dose GCs and have very low numbers of GC receptors in their mononuclear cells. This defect is irreversible in culture and affects their T cells as well as non‐T cells. The current studies provide new insights into mechanisms by which inflammation induces GC resistance and how defects in the GC receptor may contribute to chronic inflammation, creating the vicious cycle leading to chronic inflammatory diseases.
Interleukin‐1 Receptor Defect in Autoimmune NZB Mouse Brain
Authors: HAOUR FRANCE , JAFARIAN‐TEHRANI MEHRNAZ , GABELLEC MARIE‐MADELEINE , CRUMEYROLLE‐ARIAS MICHELE , HU YANHUA , WICK GEORG , TERNYNCK THERESE
Published: February 2006

Abstract: Interleukin‐1 receptors (lL‐1R type I and II) have been characterized in murine nervous structures (hippocampus and frontal cortex), in vascular structures (vessels, choroid plexus), and in the anterior pituitary. Because interleukin‐1 (IL‐ 1), injected or induced in the brain, is a powerful regulator of the stress axis and immune functions, it was of interest to investigate IL‐1Rs and IL‐1 in autoimmune mice. In control mice, bacterial lipopolysaccharide (LPS), administered i.p. or i.c.v., induces a sharp decrease in available brain IL‐1 receptors, in spite of a moderate increase in mRNAs for both receptor types. This is concomitant with an increase in IL‐1α, β, and ra mRNA. Ligand production clearly overcomes receptor turnover. In autoimmune mice (NZB and NZB/NZW F1), a strong defect in IL‐1R (type I) is demonstrated in the dentate gyrus. This tissue‐specific defect cannot be explained by increased occupancy by endogeneous ligands as for LPS‐treated mice. The transmission of the defect is Mendelian and suggests the involvement of a single gene. However patterns of IL‐1R mRNAs (evaluated by RT‐PCR) are similar in NZB and in controls, suggesting a translational or post‐translational abnormality. The contribution of this genetic disorder in the development of autoimmunity remains to be clarified. Because the brain IL‐1 system sends inhibitory signals towards immune functions, this lack of functional IL‐1 binding sites might participate in the disregulations observed in NZB autoimmune mice.
Neurohormonal Host Defense in Endotoxin Shock
Authors: BERCZI ISTVAN
Published: February 2006

Abstract: Lipopolysaccharide (LPS) of gram‐negative bacteria is capable of activating the immune system of higher animals, which may lead to cytokine‐induced lethal shock and death. LPS has little toxicity for the frog and fish, but it kills the horseshoe crab instantly by causing intravascular blood coagulation. The response to LPS evolved from simple reactions in lower animals into an intense reaction in mammals that involves a massive immune activation leading to a profound neuroendocrine and metabolic response. This is now known as the acute‐phase response (APR). During APR, LPS‐binding proteins (LBP) are produced by the liver in rapidly increasing quantities under the influence of interleukin‐6, glucocorticoids, and catecholamines. After combination with LPS, LPB is capable of activating monocyte‐macrophages and granulocytes via the CD14 surface receptor. Other receptors (CD18, 80‐kDa receptor) allow for direct action by LPS of phagocytes, B and T lymphocytes, and other cells. Numerous other acute‐phase proteins are produced in the liver, including C‐reactive protein, complement components, fibrinogen, enzyme inhibitors, and anti‐inflammatory proteins. Similar responses may be stimulated by subtoxic doses of LPS or by detoxified LPS, which manifest in endotoxin tolerance. Tolerant animals and man show increased resistance to LPS, to infections, and to various noxious insults. Infection and various forms of tissue injury are also capable of causing APR. There is much evidence to indicate that APR, which manifests in febrile illness, is an efficient host defense reaction. It is an emergency response in cases where specific immunity fails to protect the host. Therefore, the neuroimmunoregulatory network converts the immune system to a less specific, but rapid and more efficient response, APR. The hypothesis is presented that intestinal LPS serves to amplify the APR in response to various insults, which contribute to host defense, regeneration, and healing.
Stress‐Induced Neuroendocrine Modulation of Viral Pathogenesis and Immunitya
Authors: SHERIDAN JOHN F. , DOBBS CATHLEEN , JUNG JAEHO , CHU XIAOHONG , KONSTANTINOS ALEXANDRIA , PADGETT DAVID , GLASER RONALD
Published: February 2006

Abstract: Physical restraint (RST) was used to examine the interactions among the hypothalamic‐pituitary‐adrenal (HPA) axis, sympathetic nervous system, and the immune response to infection. In these studies, mice were infected with either herpes simplex virus (HSV) or influenza A/PR8 virus so that the impact of neuroendocrine activation could be assessed on disease pathophysiology and anti‐viral immunity. RST suppressed lymphadenopathy in draining lymph nodes, reduced mononuclear cellular infiltration in the lungs, and suppressed virus‐specific cytokine and cytolytic T‐cell responses. Blockade of type II glucocorticoid receptors (by RU486) restored cellularity and cytokine responses to both organs in restraint‐stressed, infected mice. Thus, the HPA axis modulated cell trafficking and T‐cell cytokine responses. However, RU486 treatment failed to restore cytolytic T‐cell responses. Blockade of β‐adrenergic receptors (by nadolol), in combination with RU486 treatment, fully restored cytolytic T‐cell responses, suggesting that catecholamines were involved in suppressing the virus‐specific CD8+ cytolytic T‐cell response. RST also modulated the local development or expression of antibody‐secreting cells (ASC) in the lungs draining lymph nodes, and spleen following infection of restrained mice. RST significantly suppressed the number of virus‐specific ASC (IgM, IgG and subclasses IgG1 and IgG2a) in the lungs, mediastinal (MLN) lymph nodes and spleen, while it enhanced the responses in the superficial cervical (SCV) lymph nodes. This observation of differential modulation of ASC responses in the MLN and SCV lymph nodes supports the concept of tissue‐specific immunoregulation in response to stress.
Neuroendocrine Dysfunction in African Trypanosomiasis: The Role of Cytokinesa
Authors: REINCKE MARTIN , ARLT WIEBKE , HEPPNER CHRISTINA , PETZKE FRANK , CHROUSOS GEORGE P. , ALLOLIO BRUNO
Published: February 2006

Abstract: Sleeping sickness (SS; African trypanosomiasis) is an anthropozoonosis transmitted by the tsetse fly. Infection with Trypanosoma brucei in humans is associated with adynamia, lethargy, anorexia, and more specifically amenorrhea/infertility in women and loss of libido/impotence in men. Recent evidence suggests that experimental infection in animals with Trypanosoma brucei species causes polyglandular endocrine failure by local inflammation of the pituitary, thyroid, adrenal, and gonadal glands. In a cross‐sectional study we investigated the prevalence and significance of neuroendocrine abnormalities in 137 Ugandan patients with SS. In the untreated stage of the disease, there was a high prevalence of adrenal insufficiency (27%), hypothyroidism (50%) and hypogonadism (85%). Pituitary function tests suggested an unusual combined central (hypothalamic/pituitary) and peripheral defect in hormone secretion. Specific therapy resulted in a rapid recovery of adrenal/thyroid function, whereas hypogonadism persisted for years in a substantial portion of patients. We did not detect pituitary, thyroid, adrenal, and gonadal autoantibodies in patients with endocrine dysfunction, ruling out an autoimmune origin of the endocrine abnormalities. However, the presence of hypopituitarism correlated with high cytokine concentrations (TNF‐alpha, IL‐6) which‐together with direct parasitic infiltration of the endocrine glands‐are involved in the pathogenesis of SS‐associated endocrine dysfunction.
Multifunctional Lens Crystallins and Corneal Enzymes: More than Meets the Eye
Authors: PIATIGORSKY JORAM
Published: February 2006

Abstract: The abundant water‐soluble proteins, called crystallins, of the transparent, refractive eye lens have been recruited from metabolic enzymes and stress‐protective proteins by a process called “gene sharing.” Many crystallins are also present at lower concentration in nonocular tissues where they have nonrefractive roles. The complex expression pattern of the mouse αB‐crystallin/small heat shock protein gene is developmentally controlled at the transcriptional level by a combinatorial use of shared and lens‐specific regulatory elements. A number of crystallin genes, including that for αB‐crystallin, are activated by Pax‐6, a conserved transcription factor for eye evolution. Aldehyde dehydrogenase class 3 and transketolase are metabolic enzymes comprising extremely high proportions of the water‐soluble proteins of the cornea and may have structural as well as enzymatic roles, reminiscent of lens enzyme‐crystallins. Inductive processes appear to be important for the corneal‐preferred expression of these enzymes. The use of the same protein for entirely different functions by a gene‐sharing mechanism may be a general strategy based on evolutionary tinkering at the level of gene regulation.
The Roles of Stably Committed and Uncommitted Cells in Establishing Tissues of the Somite
Authors: GEORGE‐WEINSTEIN MINDY , GERHART JACQUELYN , MATTIACCI‐PAESSLER MICHELE , SIMAK EILEEN , BLITZ JENNIFER , REED REBECCA , KNUDSEN KAREN
Published: February 2006

Abstract: Somites are blocks of embryonic mesoderm tissue that give rise to skeletal muscle, cartilage, and other connective tissues. The development of different tissues within the somite is influenced by adjacent structures, in particular, the neural tube and notochord. Results of experiments performed in vivo and in vitro suggest that somites contain populations of cells stably programmed to undergo either skeletal myogenesis or chondrogenesis and a population uncommitted to either pathway. The fate of the uncommitted cells would depend on a transfer of information from the committed cells. Communication between committed and uncommitted cells is regulated by cell and tissue interactions that either activate or inhibit this process.