Glucocorticoid receptor signaling in the intestinal epithelial cell lines IEC-6 and Caco-2:: evidence of inhibition by interleukin-1β

Background and aims: Glucocorticoids are potent anti-inflammatory drugs widely used in the treatment of inflammatory bowel disease, but many patients do not benefit from glucocorticoid therapy (glucocorticoid resistance) or need inappropriately high doses to retain remission (glucocorticoid dependency). Because of the role of intestinal epithelial cells in inflammatory bowel disease we examined glucocorticoid receptor signaling and the effect of interleukin-1 beta as one of the main proinflammatory cytokines in the intestinal epithelial cell lines IEC-6 and Caco-2. Methods: Dexamethasone effects on transcriptional activation was measured by reporter gene assay using a construct containing glucocorticoid-responsive elements. The transrepressive effect was monitored by a nuclear factor (NF) kappaB inducible reporter construct. In addition in IEC-6 cells immuncytochemistry was used to monitor glucocorticoid receptor translocation. Results: Dexamethasone induced receptor-mediated reporter gene transcription and receptor translocation, while interleukin-1 beta significantly inhibited dexamethasone effects. Dexamethasone inhibited interleukin-1 beta induced, NF-kappaB driven gene transcription only in IEC-6 and not in Caco-2 cells. However, in Caco-2 cells glucocorticoid receptor overexpression resulted in a marked decrease in NF-kappaB activity even in absence of dexamethasone. Conclusions: These studies demonstrate that glucocorticoid receptor driven gene regulation in intestinal epithelial cells may contribute to the anti-inflammatory effects of glucocorticoids in inflammatory bowel disease. Our data are consistent with the notion that interleukin-1 beta produced during inflammatory response induces steroid resistance, which is a common clinical problem in treating patients with inflammatory bowel disease.