Epithelial deletion of the glucocorticoid receptor protects the mouse intestine against experimental inflammation

Abstract

Intestinal epithelium glucocorticoid receptor knockout mice (NR3C1 IEC) were treated with dextran sulfate sodium (DSS, 2.5%) to induce colitis. Inflammatory status was assessed by morphological and biochemical methods and corticoid production was measured in colonic explants. Key Results. After 7 days of DSS NR3C1 mice exhibited lower weight loss and tissue damage, reduced colonic expression of S100A9, attenuated phosphorylation of STAT3 and a better overall state compared with WT. Ki67 immunoreactivity was also shifted, indicating an effect on epithelial proliferation. A subgroup of mice were treated with budesonide and showed completely prevented budesonide induced weight loss. Epithelial deletion of the glucocorticoid receptor also protected mice in a protracted colitis protocol. Conversely knockout mice presented a worse status compared to the control group at 1 day post DSS, as shown by blood in feces and increased inflammatory parameters. In a separate experiment colonic corticosterone production was shown to be significantly increased in knockout mice at 7 days of colitis but not at earlier stages. Conclusions and Implications. The intestinal epithelial glucocorticoid receptor has deleterious effects in experimental colitis induced by dextran sodium sulfate, probably related to inhibition of epithelial proliferative responses leading to impaired wound healing and reduced endogenous corticosterone production.