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 corticotropinreleasing 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.

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…They also exhibit impaired spatial memory but normal anxiety-like behavior [38]. Mice that overexpress the glucocorticoid receptor (YGR mice) have a marked decrease in hypothalamic CRH and pituitary POMC expression, increased plasma ACTH levels, and decreased plasma corticosterone levels [39]. To date, there are no reports on behavioral studies carried out in these mice.…”

Nontranscriptional actions of the glucocorticoid receptor

“…Mice lacking GR (GR −/− ) die shortly after birth due to impaired maturation of several organs including the lungs [46]. In contrast, overexpression of GR renders mice resistant to stress and endotoxic shock, which seem to involve a decrease in the inflammatory response [47]. While the absence of GR is incompatible with life, DNA binding and transactivation of target genes by GR is not essential for development or survival.…”

Cross-talk between glucocorticoid receptor and AP-1

“…Removal of the adrenal gland, the site of cortisol production, as well as manipulation of the levels of the glucocorticoid receptor (see below) sensitizes the organism for exaggerated immune responses including septic shock (e.g. Miller and Blake Tyrrel, 1995;Barnes, 1998;Reichardt et al, 2000). Glucocorticoid hormone downregulates the septic shock response and counteracts in¯ammatory and immune as well as autoimmune reactions in general which makes glucocorticoids one of the most frequently prescribed drugs.…”