Intestinal epithelial deletion of the glucocorticoid receptor NR3C1 alters expression of inflammatory mediators and barrier function

Abstract

Glucocorticoids (GC) are important hormones involved in the regulation of multiple physiological functions. GC are also widely used antiinflammatory/immunosuppresant drugs. GC are synthesized by the adrenal cortex as part of the hypothalamus-pituitary-adrenal axis, and also by intestinal epithelial cells, among other peripheral sites. GC are one of the main therapy choices for the exacerbations of inflammatory bowel disease, but they are not useful to prolong remission, and development of tolerance with secondary treatment failure is frequent. Thus GC actions at the intestinal epithelial level are of great importance, both physiologically and pharmacologically. We generated a tamoxifen inducible NR3C1IEC model to study the effects of GC on epithelial cells in vivo. Nr3c1 deletion in epithelial cells of the small intestine and colon was associated with limited colonic inflammation at 1 week postdeletion, involving augmented epithelial proliferation and mucus production, plus local and systemic immune/inflammatory changes. This phenotype regressed substantially, but not completely, after 2 weeks. The mechanism may involve augmented inflammatory signaling by epithelial cells and/or defective barrier function. We conclude that the epithelial GC receptor plays a significant role in colonic homeostasis in basal conditions, but its deficiency can be compensated in the short term. Future studies are required to assess the impact of Nr3c1 deletion in other conditions such as experimental colitis.