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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 32; pp. 13098 - 13103
• Main Authors: Coste, Agnes, Dubuquoy, Laurent, Barnouin, Romain, Annicotte, Jean-Sebastien, Magnier, Benjamin, Notti, Mario, Corazza, Nadia, Antal, Maria Cristina, Metzger, Daniel, Desreumaux, Pierre, Brunner, Thomas, Auwerx, Johan, Schoonjans, Kristina
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.08.2007; National Acad Sciences
• Subjects: Adult; Biochemistry, Molecular Biology; Biological Sciences; Biopsies; Cells; Cholesterol Side-Chain Cleavage Enzyme; Cholesterol Side-Chain Cleavage Enzyme - genetics; Colitis; Colon; Corticosterone; Corticosterone - biosynthesis; DNA-Binding Proteins; DNA-Binding Proteins - physiology; Enterocytes; Enterocytes - metabolism; Enzymes; Female; Gene expression; Glucocorticoids; Glucocorticoids - biosynthesis; Hormones; Humans; Inflammation; Inflammatory bowel disease; Inflammatory Bowel Diseases; Inflammatory Bowel Diseases - prevention & control; Intestinal mucosa; Life Sciences; Lipids; Male; Messenger RNA; Mice; Middle Aged; Molecular biology; Receptors, Cytoplasmic and Nuclear; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Messenger; RNA, Messenger - analysis; Steroid 11-beta-Hydroxylase; Steroid 11-beta-Hydroxylase - genetics; Transcription Factors; Transcription Factors - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0702440104

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.