Neuroendocrine Stress Response in Inflammatory &Behavio

National Institute Of Mental Health

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Abstract

The research of the Section on Neuroendocrine Immunology and Behavior (SNIB) focuses on (Project 1) molecular basis of differential hypothalamic pituitary adrenal (HPA) axis regulation in inbred rat strains and its relationship to inflammatory disease susceptibility and (Project 2) repression of the glucocorticoid receptor and other nuclear hormone receptors by Bacillus anthracis (anthrax) lethal toxin (LeTx) and its role in inflammatory shock. In Project 1, we have begun to explore the expression within the brain of immune molecules (cytokines and chemokines) in rodents exposed to bacterial cell wall products. Preliminary results indicate that certain immune molecules (chemokines) are expressed within the brain under these conditions. Project 2 focuses on validation and elucidation of the molecular mechanisms and therapeutic implications of our 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. We 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. Since GR antagonists or interruptions of the hypothalamic-pituitary-adrenal (HPA) axis render otherwise shock-resistant animals highly susceptible to the lethal effects of many bacterial products, we postulated that LeTx repression of GR and other nuclear hormone receptors might contribute to anthrax toxicity and lethality. In subsequent studies we have shown that interruption of the HPA axis by adrenalectomy is associated with enhanced LeTx mortality in otherwise LeTx resistant mouse strains. Furthermore, treatment of mice with glucorticoids was associated with enhanced mortality. Follow-up molecular studies show selective repression of nuclear hormone receptors that is partially receptor and partially promoter dependent. Chromatin immunoprecipitation (ChIP) experiments indicate that LeTx inhibits GR binding to the promoter, resulting in loss of both polymerase II binding and acetylation of histone H3 in target genes. Electrophoretic mobility shift assays (EMSA) indicate that this inhibition is not due to direct interaction of LF ? PA with the GR-GRE complex. Taken together, these findings indicate that LeTx represses GR activity through its effects on co-factor(s), or modification of the receptor. These findings together with the in vivo studies indicate that an intact HPA axis (neuroendocrine response) is required for resistance to anthrax lethal toxin, and that simple glucocorticoid replacement may not be sufficient and might be detrimental as a therapy for anthrax LeTx shock.