Mice with an Increased Glucocorticoid Receptor Gene Dosage Show Enhanced Resistance to Stress and Endotoxic Shock

• DOI: 10.1128/mcb.20.23.9009-9017.2000
• Publication Date: 2002-07-27T10:03:53Z
• Authors: Holger M. Reichardt; Thorsten Umland; Anton Bauer; Oliver Kretz; Günther Schütz
• Keywords: Restraint, Physical; 0301 basic medicine; Hypothalamo-Hypophyseal System; Dose-Response Relationship, Drug; Corticotropin-Releasing Hormone; Gene Dosage; Pituitary-Adrenal System; Apoptosis; Mice, Transgenic; Thymus Gland; Neurosecretory Systems; Shock, Septic; Dexamethasone; 3. Good health; Mice; 03 medical and health sciences; Receptors, Glucocorticoid; Adrenocorticotropic Hormone; Stress, Physiological; Animals; Chromosomes, Artificial, Yeast; Glucocorticoids

Targeted mutagenesis of the glucocorticoid receptor has revealed an essential function for survival and regulation multiple physiological processes. To investigate effects increased gene dosage receptor, we have generated transgenic mice carrying two additional copies by using a yeast artificial chromosome. Interestingly, overexpression alters basal hypothalamo-pituitary-adrenal axis, resulting in reduced expression corticotropin-releasing hormone adrenocorticotrope fourfold reduction level circulating glucocorticoids. In addition, primary thymocytes obtained from show enhanced sensitivity to glucocorticoid-induced apoptosis. Finally, analysis these under challenge conditions that above wild-type levels leads weaker response restraint stress strongly resistance lipopolysaccharide-induced endotoxic shock. These results underscore importance tight control pathological Furthermore, they may explain differences susceptibility humans inflammatory diseases stress, depending on individual prenatal postnatal experiences known influence receptor.