Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

National Institute Of Mental Health

Investigators

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Abstract

The research of the Section on Neuroendocrine Immunology and Behavior (SNIB) focuses on mechanisms of glucocorticoid resistance in inflammatory, infectious and mood disorders, using repression of the glucocorticoid receptor (GR) and other nuclear hormone receptors (NHRs) by bacterial toxins as a model for study of environmentally induced glucocorticoid resistance. We initially showed that Bacillus anthracis (anthrax) lethal toxin (LeTx) repressed the GR and other NHRs and are currently studying the effects of other bacterial toxins on the GR and NHRs and the role of this effect in inflammatory shock (Project 1). In Project 2 we are studying the effects of progesterone on innate inflammatory cell responses, specifically dendritic cells, to determine whether the status of another nuclear hormone receptor, the progesterone receptor (PR) contributes to females susceptibility to such conditions. In a clinical study (Project 3) we have validated a method to measure stress and immune biomarkers in sweat in normal controls and are currently extending this validation to clinical studies in other populations, including women with Major Depressive Disorder (MDD).[unreadable] [unreadable] In Project 1, we are extending our research based on our initial finding that B. anthracis LeTx is a potent and selective repressor of nuclear hormone receptors (NHRs), including the glucocorticoid and progesterone receptors (GR and PR). These findings have important implications for treatment and prevention of toxicity and lethality from the anthrax LeTx and other bacterial toxins but also will help to elucidate molecular mechanisms of environmentally induced glucocorticoid resistance. Our current studies focus on (a) elucidation of the molecular mechanisms of this effect; (b) determination of the degree to which this effect extends to other bacterial toxins; (c) determination of the in vivo correlates of this in vitro effect; and (d) clinical and therapeutic implications. Molecular studies indicate that bacterial toxin repression of NHRs is both receptor and promoter dependent, with LeTx showing a greater repression of complex promoters (such as the MMTV promoter) compared to a simple GRE promoter. In our most recent studies we have determined that the NHR repressive effect extends to other bacterial toxins, including Clostridium sordellii lethal toxin (TcsL) and Clostridium difficile Toxins A and B (TcdA and TcdB). As with LeTx, this effect is highly sensitive (ng/ml concentrations) and non-competitive. Since bacterial toxins that do not affect the p38 MAP kinase pathway do not exhibit this effect, we postulate that p38 plays a role in bacterial toxin repression of NHRs. Furthermore, in vitro studies show that TcsL prevents dexamethasone suppression of TNF-alpha production by splenocytes in a dose-related manner, indicating that the GR repressive effect of TcsL may have functional relevance in preventing glucocorticoids anti-inflammatory effects. Current studies are aimed at further defining the molecular pathways involved in glucocorticoid resistance in this system, as well as at determining whether the in vitro effects are relevant to in vivo effects of these toxins, and testing potential therapeutic agents in both in vitro and in vivo systems. In a parallel human tissue study we are also evaluating glucocorticoid receptor polymorphisms, which we and others have shown are associated with glucocorticoid resistance in a variety of clinical conditions.[unreadable] [unreadable] In order to determine whether the bacterial toxin repression of PR might have functional relevance to inflammation, Project 2 is evaluating the effects of progesterone on dendritic cell (DC) function and maturation. We have found that progesterone, in pregnancy-associated concentrations and through a PR-mediated mechanism, suppresses mature DC production of pro-inflammatory cytokines, co-stimulatory molecule expression, and T cell proliferation by these cells but has little effect on immature DC antigen uptake. These effects, which are comparable to the effects of glucocorticoids on these parameters of DC function, suggest that progesterone may play an important role in regulation of innate and adaptive immunity during the hormonal cycle in females. Current studies are focusing on determining whether these in vitro findings are modified in such in vivo conditions, e.g. throughout the estrus cycle in rodents, and if there are differences in progesterone effects on DCs from lymphoid organs (bone marrow, spleen, lymph node) compared to DCs from organs with known progesterone sensitivity (uterus). [unreadable] [unreadable] In Project 3 we have validated a method for measuring immune and stress neuropeptide biomarkers in sweat, collected using skin sweat patches and assayed using recycling immunoaffinity chromatography and confirmed with mass spectrometry and MALDI-TOF, in collaboration with Terry Phillips, NIBIB, NIH. Current studies are applying this method to larger numbers of subjects in a variety of psychiatric disorders, including MDD and obsessive compulsive disorder in ambulatory settings. Our recent findings, (manuscript in review and abstract presented at the Endocrine Society, 2007) indicate that women with MDD show significant elevations in a battery of pro-inflammatory cytokines as well as concurrent changes in several stress neuropeptide biomarkers in sweat and plasma. These findings have important implications for the increased morbidity in MDD of inflammation-related illnesses, including osteoporosis and cardiovascular disease.