LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Coste, Agnes; Dubuquoy, Laurent; Barnouin, Romain; Annicotte, Jean-Sebastien; Magnier, Benjamin; Noti, Mario; Corazza, Nadia; Antal, Maria Cristina; Metzger, Daniel; Desreumaux, Pierre; Brunner, Thomas; Auwerx, Johan; Schoonjans, Kristina (2007). LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 104(32), pp. 13098-13103. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.0702440104

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Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in intestinal lipid homeostasis and cell proliferation. Here we show that haploinsufficiency of LRH-1 predisposes mice to the development of intestinal inflammation. Besides the increased inflammatory response, LRH-1 heterozygous mice exposed to 2,4,6-trinitrobenzene sulfonic acid show lower local corticosterone production as a result of an impaired intestinal expression of the enzymes CYP11A1 and CYP11B1, which control the local synthesis of corticosterone in the intestine. Local glucocorticoid production is strictly enterocyte-dependent because it is robustly reduced in epithelium-specific LRH-1-deficient mice. Consistent with these findings, colon biopsies of patients with Crohn's disease and ulcerative colitis show reduced expression of LRH-1 and genes involved in the production of glucocorticoids. Hence, LRH-1 regulates intestinal immunity in response to immunological stress by triggering local glucocorticoid production. These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease.

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