Tags

Type your tag names separated by a space and hit enter

Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells.
Am J Physiol Endocrinol Metab. 2009 Feb; 296(2):E367-77.AJ

Abstract

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

Authors+Show Affiliations

Depts. of Nephrology and Hypertension and Clinical Research, Freiburgstrasse 15, Univ. Hospital, Berne, CH-3010 Berne, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19088256

Citation

Ignatova, Irena D., et al. "Tumor Necrosis Factor-alpha Upregulates 11beta-hydroxysteroid Dehydrogenase Type 1 Expression By CCAAT/enhancer Binding Protein-beta in HepG2 Cells." American Journal of Physiology. Endocrinology and Metabolism, vol. 296, no. 2, 2009, pp. E367-77.
Ignatova ID, Kostadinova RM, Goldring CE, et al. Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells. Am J Physiol Endocrinol Metab. 2009;296(2):E367-77.
Ignatova, I. D., Kostadinova, R. M., Goldring, C. E., Nawrocki, A. R., Frey, F. J., & Frey, B. M. (2009). Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells. American Journal of Physiology. Endocrinology and Metabolism, 296(2), E367-77. https://doi.org/10.1152/ajpendo.90531.2008
Ignatova ID, et al. Tumor Necrosis Factor-alpha Upregulates 11beta-hydroxysteroid Dehydrogenase Type 1 Expression By CCAAT/enhancer Binding Protein-beta in HepG2 Cells. Am J Physiol Endocrinol Metab. 2009;296(2):E367-77. PubMed PMID: 19088256.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells. AU - Ignatova,Irena D, AU - Kostadinova,Radina M, AU - Goldring,Christopher E, AU - Nawrocki,Andrea R, AU - Frey,Felix J, AU - Frey,Brigitte M, Y1 - 2008/12/16/ PY - 2008/12/18/entrez PY - 2008/12/18/pubmed PY - 2009/2/28/medline SP - E367 EP - 77 JF - American journal of physiology. Endocrinology and metabolism JO - Am J Physiol Endocrinol Metab VL - 296 IS - 2 N2 - The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of inactive to active glucocorticoids. 11beta-HSD1 plays a crucial role in the pathogenesis of obesity and controls glucocorticoid actions in inflammation. Several studies have demonstrated that TNF-alpha increases 11beta-HSD1 mRNA and activity in various cell models. Here, we demonstrate that mRNA and activity of 11beta-HSD1 is increased in liver tissue from transgenic mice overexpressing TNF-alpha, indicating that this effect also occurs in vivo. To dissect the molecular mechanism of this increase, we investigated basal and TNF-alpha-induced transcription of the 11beta-HSD1 gene (HSD11B1) in HepG2 cells. We found that TNF-alpha acts via p38 MAPK pathway. Transient transfections with variable lengths of human HSD11B1 promoter revealed highest activity with or without TNF-alpha in the proximal promoter region (-180 to +74). Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-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/EBPalpha, but also C/EBPbeta, in basal and only of C/EBPbeta in the TNF-alpha-induced HSD11B1 expression. Chromatin immunoprecipitation assay confirmed in vivo the increased abundance of C/EBPbeta on the proximal HSD11B1 promoter upon TNF-alpha treatment. In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter. To our knowledge, this is the first study showing involvement of p38 MAPK in the TNF-alpha-mediated 11beta-HSD1 regulation, and that TNF-alpha stimulates enzyme activity in vivo. SN - 0193-1849 UR - https://www.unboundmedicine.com/medline/citation/19088256/Tumor_necrosis_factor_alpha_upregulates_11beta_hydroxysteroid_dehydrogenase_type_1_expression_by_CCAAT/enhancer_binding_protein_beta_in_HepG2_cells_ L2 - https://journals.physiology.org/doi/10.1152/ajpendo.90531.2008?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -