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, our prior genetic linkage and segregation studies identified a region on chromosome 10, containing the CRH receptor type 1 (CRH-R1) gene, that linked to inflammatory susceptibility and resistance in relatively HPA axis hypo- and hyper-responsive inbred LEW/N and F344/N rats. Sequencing of the CRH-R1coding region showed no differences in these strains and hypothalamic CRH-R1 mRNA was not differentially regulated, indicating that the CRH-R1 gene is unlikely to be the source of the differential phenotypes in these strains. Expression microarray studies and real-time RT-PCR of hypothalamic tissue pre- and post-bacterial lipopolysaccharide (LPS) treatment indicated differential transthyretin (TTR) and cholecystokinin (CCK) mRNA expression, suggesting a possible role for thyroid hormone dysregulation, since TTR is a major thyroid hormone transporter. Both immunoaffinity capillary electrophoresis protein quantitation and real-time RT-PCR mRNA in rat fetal hypothalamic tissue indicated that CRH and AVP secretion and pro-inflammatory cytokines are up-regulated in LEW/N fetal hypothalamic tissue. In GR studies, we found a polymorphism associated with enhanced stability of the GRb in human rheumatoid arthritis patients that could lead to relative glucocorticoid resistance in these patients. Most recently we found 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)a but not the mineralocorticoid receptor (MR) or ERb. 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 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). The role of this repression in anthrax toxicity remains to be determined.
| Thayer, Julian F; Verkuil, Bart; Brosschot, Jos F et al. (2010) Effects of the physical work environment on physiological measures of stress. Eur J Cardiovasc Prev Rehabil 17:431-9 |
| Butts, Cherie L; Bowers, Eve; Horn, J Cash et al. (2008) Inhibitory effects of progesterone differ in dendritic cells from female and male rodents. Gend Med 5:434-47 |
| Butts, Cherie L; Shukair, Shetha A; Duncan, Kristina M et al. (2007) Evaluation of steroid hormone receptor protein expression in intact cells using flow cytometry. Nucl Recept Signal 5:e007 |
| Tait, A Sasha; Dalton, Monique; Geny, Blandine et al. (2007) The large clostridial toxins from Clostridium sordellii and C. difficile repress glucocorticoid receptor activity. Infect Immun 75:3935-40 |
| Eskandari, Farideh; Martinez, Pedro E; Torvik, Sara et al. (2007) Low bone mass in premenopausal women with depression. Arch Intern Med 167:2329-36 |
| Marques, Andrea H; Cizza, Giovanni; Sternberg, Esther (2007) [Brain-immune interactions and implications in psychiatric disorders] Rev Bras Psiquiatr 29 Suppl 1:S27-32 |
| Sternberg, Esther M; Silverman, Marni N; Cizza, Giovanni (2007) The neuroendocrine system and rheumatoid arthritis: insights from anti-tumor necrosis factor-alpha therapy. J Rheumatol 34:1443-5 |
| Butts, C L; Shukair, S A; Duncan, K M et al. (2007) Effects of dexamethasone on rat dendritic cell function. Horm Metab Res 39:404-12 |
| Butts, Cherie L; Shukair, Shetha A; Duncan, Kristina M et al. (2007) Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion. Int Immunol 19:287-96 |
| Sternberg, Esther M (2006) Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6:318-28 |
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