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

Abstract

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-α 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-α, indicating that this effect also occurs in vivo. To dissect the molecular mechanism of this increase, we investigated basal and TNF-α-induced transcription of the 11β-HSD1 gene ( HSD11B1) in HepG2 cells. We found that TNF-α acts via p38 MAPK pathway. Transient transfections with variable lengths of human HSD11B1 promoter revealed highest activity with or without TNF-α in the proximal promoter region (−180 to +74). Cotransfection with human CCAAT/enhancer binding protein-α (C/EBPα) 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/EBPα, but also C/EBPβ, in basal and only of C/EBPβ in the TNF-α-induced HSD11B1 expression. Chromatin immunoprecipitation assay confirmed in vivo the increased abundance of C/EBPβ on the proximal HSD11B1 promoter upon TNF-α treatment. In conclusion, C/EBPα and C/EBPβ control basal transcription, and TNF-α 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-α-mediated 11β-HSD1 regulation, and that TNF-α stimulates enzyme activity in vivo.

Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats

“…Thus, time-course studies after UNX in the remaining kidney must be performed in order to identify relevant regulatory factors for the expression of 11b-HSD1 and 11b-HSD2. A number of factors regulating the expression of 11b-HSD enzymes have previously been identified including TNF-a, Erg1, NF-kB, NF1, C/EBPs, GR, Sp1/Sp3, Arnt, PPAR-a/PPAR-g, IL1, glucocorticoids, sex steroids, and thyroid hormones (Alikhani-Koopaei et al 2004, Tomlinson et al 2004, Kostadinova et al 2005, Alikhani-Koupaei et al 2007, Wake et al 2007, Ignatova et al 2009). The ultimate proof for a pivotal relevance of one or a combination of these factors would require the investigation of animals with specific over-or under-expression in the cortical collecting duct.…”

Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo

“…The regulation of the activities of HSD11B1 and HSD11B2 enzymes by different endogenous molecules, xenobiotics, and in various disease states has been described previously; it appears to be clinically relevant (Escher et al 1997, 1998a,b, Fuster et al 1998, Quattropani et al 2001, Heiniger et al 2003, Kostadinova et al 2005, Ignatova et al 2009, Konopelska et al 2009). Herein, we report a novel player, 27-OHC, which regulates the activity of these key enzymes, thereby determining the intracellular availability of glucocorticoids.…”

“…With the ultimate goal of treating and/or preventing the metabolic syndrome, an array of exogenous compounds inhibiting the activity of HSD11B1 have been synthesised (Boyle & Kowalski 2009), and the role of endogenous compounds including insulin, glucocorticoids, TNFa, and bile acids and their molecular mechanisms in the regulation of the expression and activity of HSD11B have been reported (Escher et al 1997, Ackermann et al 1999, Williams et al 2000, Quattropani et al 2001, Kostadinova et al 2005, Balachandran et al 2008, Ignatova et al 2009). Thus, understanding the factors regulating the activity of this enzyme is of potential clinical importance.…”

Inhibition of 11β-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice

“…Although 11b-HSD1 expression also plays an important role in the development of metabolic syndromes, in recent years pharmacological interventions targeting 11b-HSD1 have mainly focused on the inhibition of 11b-HSD1 enzymatic activity. Several stimuli, including HG, TNF-a, and lipopolysaccharide (LPS) have been shown to stimulate the expression of 11b-HSD1 in different cells (Ishii et al 2007, Ignatova et al 2009, Fan et al 2011. It has been reported that TNF-a-induced 11b-HSD1 expression was mediated by p38 MAPK, CCAAT/ enhancer binding protein (C/EBP)-b, and NF-kB pathways (Ignatova et al 2009).…”