HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/2/E367    most recent 90531.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ignatova, I. D. Articles by Frey, B. M. Search for Related Content PubMed PubMed Citation Articles by Ignatova, I. D. Articles by Frey, B. M.

Tumor necrosis factor- upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells

Departments of Nephrology and Hypertension and Clinical Research, University Hospital, Berne, Berne, Switzerland

Submitted 23 June 2008 ; accepted in final form 8 December 2008

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive to active glucocorticoids. 11β-HSD1 plays a crucial role in the pathogenesis of obesity and controls glucocorticoid actions in inflammation. Several studies have demonstrated that TNF- increases 11β-HSD1 mRNA and activity in various cell models. Here, we demonstrate that mRNA and activity of 11β-HSD1 is increased in liver tissue from transgenic mice overexpressing TNF-, indicating that this effect also occurs in vivo. To dissect the molecular mechanism of this increase, we investigated basal and TNF--induced transcription of the 11β-HSD1 gene (HSD11B1) in HepG2 cells. We found that TNF- acts via p38 MAPK pathway. Transient transfections with variable lengths of human HSD11B1 promoter revealed highest activity with or without TNF- in the proximal promoter region (–180 to +74). Cotransfection with human CCAAT/enhancer binding protein- (C/EBP) and C/EBPβ-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region. Gel shift and RNA interference assays revealed the involvement of mainly C/EBP, but also C/EBPβ, in basal and only of C/EBPβ in the TNF--induced HSD11B1 expression. Chromatin immunoprecipitation assay confirmed in vivo the increased abundance of C/EBPβ on the proximal HSD11B1 promoter upon TNF- treatment. In conclusion, C/EBP and C/EBPβ control basal transcription, and TNF- upregulates 11β-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPβ to the human HSD11B1 promoter. To our knowledge, this is the first study showing involvement of p38 MAPK in the TNF--mediated 11β-HSD1 regulation, and that TNF- stimulates enzyme activity in vivo.

p38 mitogen-activated protein kinase; chromatin immunoprecipitation; RNA interference