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

Abstract

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

ACKNOWLEDGMENTS

We thank Brenda Stride for careful reading of the manuscript and Heike Glaser and Nadine Sold for expert technical assistance.

This work was supported by the Deutsche Forschungsgemeinschaft through SFB 405; by the Fonds der Chemischen Industrie; by the European Community, through the grants PL 96 0179 and Marie Curie QLK2-CD-1999-51404; by the BMBF through the HGP grant 01 KW 9606/7; by the Hermann von Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF); by the Alexander von Humboldt-Stiftung; by the Volkswagen-Stiftung; and by Boehringer Ingelheim.

H.M.R. and T.U. contributed equally to this work.