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Glucocorticoid Regulation of the Promoter of 11β-Hydroxysteroid Dehydrogenase Type 1 Is Indirect and Requires CCAAT/Enhancer-Binding Protein-β

Endocrinology Unit (S.S., C.L.E., V.K., Z.M., K.A., J.R.S., K.E.C.), Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Department of Pediatrics (S.S., Y.N., T.O.), Hamamatsu University, School of Medicine, Hamamatsu 431-3192, Japan; and Department of Clinical Biochemistry (A.P.C.), Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom

Address all correspondence and requests for reprints to: Karen E. Chapman, Endocrinology Unit, Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: Karen.Chapman{at}ed.ac.uk.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inert 11keto-glucocorticoids to active 11β-hydroxy forms, thereby amplifying intracellular glucocorticoid action. Up-regulation of 11β-HSD1 in adipose tissue and liver is of pathogenic importance in metabolic syndrome. However, the mechanisms controlling 11β-HSD1 transcription are poorly understood. Glucocorticoids themselves potently increase 11β-HSD1 expression in many cells, providing a potential feed-forward system to pathology. We have investigated the molecular mechanisms by which glucocorticoids regulate transcription of 11β-HSD1, exploiting an A549 cell model system in which endogenous 11β-HSD1 is expressed and is induced by dexamethasone. We show that glucocorticoid induction of 11β-HSD1 is indirect and requires new protein synthesis. A glucocorticoid-responsive region maps to between –196 and –88 with respect to the transcription start site. This region contains two binding sites for CCAAT/enhancer-binding protein (C/EBP) that together are essential for the glucocorticoid response and that bind predominantly C/EBPβ, with C/EBP present in a minority of the complexes. Both C/EBPβ and C/EBP are rapidly induced by glucocorticoids in A549 cells, but small interfering RNA-mediated knockdown shows that only C/EBPβ reduction attenuates the glucocorticoid induction of 11β-HSD1. Chromatin immunoprecipitation studies demonstrated increased binding of C/EBPβ to the 11β-HSD1 promoter in A549 cells after glucocorticoid treatment. A similar mechanism may apply in adipose tissue in vivo where increased C/EBPβ mRNA levels after glucocorticoid treatment were associated with increased 11β-HSD1 expression. C/EBPβ is a key mediator of metabolic and inflammatory signaling. Positive regulation of 11β-HSD1 by C/EBPβ may link amplification of glucocorticoid action with metabolic and inflammatory pathways and may represent an endogenous innate host-defense mechanism.

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Nuclear Receptors:   GR

Ligands:   Dexamethasone  |  RU486