Neuroendocrine Stress Response in Inflammatory/Behavior

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The research of the Section on Neuroendocrine Immunology and Behavior (SNIB) focuses on (1) molecular basis of differential hypothalamic pituitary adrenal (HPA) axis regulation in inbred rat strains and its relationship to inflammatory disease susceptibility and (2) role of the glucocorticoid receptor (GR) in autoimmune/inflammatory disease, including Bacillus anthracis (anthrax) lethal toxin (LeTx) repression of the glucocorticoid and other nuclear hormone receptors. In Project 1, we have continued to explore the molecular basis for differential hypothalamic CRH and HPA axis responses in a rodent model linking differential HPA axis responsiveness and inflammatory susceptibility. Recent studies focused on developmental differences of expression and secretion of immune and neuroendocrine molecules in rat fetal hypothalamic cells in culture. These studies (Project 1, refs 1, 2) indicate that even at the earliest stages of development, LEW/N hypothalamic cells express higher basal and stimulated levels of pro-inflammatory cytokines and related molecules (both mRNA and protein) compared to inflammatory resistant F344/N rats. These findings are consistent with new in vivo studies in adult rats showing a greater expression of IL-1beta mRNA in LEW/N compared to F344/N rats after exposure to bacterial lipopolysaccharides (Project 1, ref 3). Expression microarray and real-time RT-PCR analyses of hypothalamic tissue pre- and post in vivo intraperitoneal bacterial lipopolysaccharide (LPS) treatment showed differential transthyretin (TTR) and cholecystokinin (CCK) mRNA expression, suggesting a possible role for thyroid hormone in the differential neuroendocrine phenotypes, since TTR is a major thyroid hormone transporter. Indeed, further analysis of the thyroid axis showed differential thyroid releasing hormone (TRH) expression in these strains. Clinical studies in patients with multiple sclerosis were also consistent with animal studies linking glucocorticoid dysregulation and course and severity of CNS autoimmune disease. Thus we have identified a sub-population of MS patients showing corticosteroid resistance in an ex vivo assay (Project 1, ref 4). In Project 2, we have followed up on initial studies showing that nanomolar concentrations of Bacillus anthracis LeTx (lethal factor + protective antigen) selectively repress nuclear hormone receptor activity, including GR, the progesterone receptor (PR) and the estrogen receptor (ER) alpha but not the mineralocorticoid receptor (MR) or ER beta (Project 2, ref 1). This repression is non-competitive, and does not occur through the receptor?s ligand binding or DNA binding domains, and most likely results from LeTx selective interaction with nuclear hormone receptor co-factors. The repression is seen in vitro both in a transient transfection system and at the level of activity of a glucocorticoid regulated enzyme (hepatocyte tyrosine amino transferase, TAT), and in vivo (repression of hepatic TAT activation). Current studies further analyze the precise molecular mechanism of this effect and address the role of nuclear hormone receptor repression in anthrax toxicity.