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Cell cycle-dependent regulation of extra-adrenal glucocorticoid synthesis in murine intestinal epithelial cells

Atanas G. Atanasov^*, Dominic Leiser^*, Corinne Roesselet^*, Mario Noti^*, Nadia Corazza^*, Kristina Schoonjans and Thomas Brunner^*

^* Division of Immunopathology, Institute of Pathology, University of Bern, Bern, Switzerland; and

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, France

¹Correspondence: Division of Immunopathology, Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland. E-mail: tbrunner{at}pathology.unibe.ch

Glucocorticoids are anti-inflammatory steroids with important applications in the treatment of inflammatory diseases. Endogenous glucocorticoids are mainly produced by the adrenal glands, although there is increasing evidence for extra-adrenal sources. Recent findings show that intestinal crypt cells produce glucocorticoids, which contribute to the maintenance of intestinal immune homeostasis. Intestinal glucocorticoid synthesis is critically regulated by the transcription factor liver receptor homologue-1 (LRH-1). As expression of steroidogenic enzymes and LRH-1 is restricted to the proliferating cells of the crypts, we aimed to investigate the role of the cell cycle in the regulation of LRH-1 activity and intestinal glucocorticoid synthesis. We here show that either pharmacological or molecular modulation of cell cycle progression significantly inhibited expression of steroidogenic enzymes and synthesis of glucocorticoids in intestinal epithelial cells. Synchronization of intestinal epithelial cells in the cell cycle revealed that expression of steroidogenic enzymes is preferentially induced at the G₁/S stage. Differentiation of immature intestinal epithelial cells to mature nonproliferating cells also resulted in reduced expression of steroidogenic enzymes. This cell cycle-related effect on intestinal steroidogenesis was found to be mediated through the regulation of LRH-1 transcriptional activity. This mechanism may restrict intestinal glucocorticoid synthesis to the proliferating cells of the crypts.—Atanasov, A. G., Leiser, D., Roesselet, C., Noti, M., Corazza, N., Schoonjans, C., Brunner, T. Cell cycle-dependent regulation of extra-adrenal glucocorticoid synthesis in murine intestinal epithelial cells.

Key Words: liver receptor homologue-1 • nuclear receptors • steroidogenesis • mucosal immunology

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