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Cell cycle-dependent regulation of extra-adrenal glucocorticoid synthesis in murine intestinal epithelial cells.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2008 Dec; Vol. 22 (12), pp. 4117-25. Date of Electronic Publication: 2008 Aug 18. - Publication Year :
- 2008
-
Abstract
- 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 G(1)/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.
- Subjects :
- Animals
Aphidicolin pharmacology
CDC2 Protein Kinase physiology
Cell Cycle drug effects
Cell Differentiation
Cell Line
Cholesterol Side-Chain Cleavage Enzyme biosynthesis
Colforsin pharmacology
Cyclin B biosynthesis
Cyclin B1
Cyclin D1 biosynthesis
Doxorubicin pharmacology
Intestinal Mucosa cytology
Kinetin pharmacology
Mice
Nocodazole pharmacology
Receptors, Cytoplasmic and Nuclear physiology
Retinoblastoma Protein physiology
Steroid 11-beta-Hydroxylase biosynthesis
Transfection
Cell Cycle physiology
Glucocorticoids biosynthesis
Intestinal Mucosa metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 22
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 18711026
- Full Text :
- https://doi.org/10.1096/fj.08-114157