Role of Neuroendocrine Stress Response in Inflammatory a

National Institute Of Mental Health

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Abstract

The research of the Section on Neuroendocrine Immunology and Behavior (SNIB) has shifted to focus primarily on our discovery of the repression of the glucocorticoid receptor and other nuclear hormone receptors by Bacillus anthracis (anthrax) lethal toxin (LeTx) and other bacterial toxins and the role of this effect in inflammatory shock (Project 1). In addition we are studying the effects of progesterone on innate inflammatory cell responses, specifically dendritic cells (Project 2). In a clinical study (Project 3) we have validated a method to measure cytokines in sweat and are currently extending this validation to other clinical studies.[unreadable] In Project 1, we are extending our research based on our initial finding that Bacillus anthracis lethal toxin (LeTx) is a potent and selective repressor of nuclear hormone receptors, including the glucocorticoid receptor (GR) and progesterone receptor (PR). These findings have important implications for treatment and prevention of anthrax LeTx and other bacterial toxins? toxicity and lethality. Our current studies focus on (a) elucidation of the molecular mechanisms of this effect; (b) determination of whether this effect extends to other bacterial toxins; (c) determination of the in vivo correlates of this in vitro effect; and (d) therapeutic implications. We first followed up on initial studies showing that nanomolar concentrations of LeTx selectively repress nuclear hormone receptor activity, including the glucocorticoid receptor (GR), the progesterone receptor (PR) and the estrogen receptor (ER) alpha but not the mineralocorticoid receptor (MR) or ER beta. Molecular studies indicate that this effect is both receptor and promoter dependent, with complex promoters (MMTV) showing greater effects on many nuclear hormone receptors than the simple GRE promoter. Current studies are in progress using mutant constructs of complex promoters to identify the precise location in the promoter region that is required for these toxins? repressive effects. In other studies we have determined that this nuclear hormone receptor repressive effect extends to other bacterial toxins, including C. sordellii lethal toxin and C. difficile Toxins A and B. Current studies are aimed at determining whether these in vitro effects are relevant to in vivo effects of these toxins, as well as testing potential therapeutic agents in both in vitro and in vivo systems.[unreadable] In Project 2 we have found that progesterone, through a receptor-mediated mechanism, suppresses mature dendritic cell activation, including production of pro-inflammatory cytokines and co-stimulatory molecule expression, but has no effect on immature dendritic cells.[unreadable] In Project 3 we have validated a method for measuring immune and stress biomarkers in sweat, using skin patches and assay of samples using recycling immunoaffinity chromoatography and mass spectrometry. Current studies focus on extending these studies to include larger numbers of subjects and subjects under different conditions.