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Tumor necrosis factor alpha down-regulates expression of the alpha1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPbeta- and C/EBPdelta-dependent mechanism.
Hepatology. 2000 May; 31(5):1086-93.Hep

Abstract

Tumor necrosis factor alpha (TNF-alpha) is one of the key cytokines of the acute phase response and of many inflammatory processes. This cytokine has several antifibrogenic actions and down-regulates the expression of the type I collagen genes and induces the expression of metalloproteinases. Because TNF-alpha directly antagonizes some fibrogenic actions of transforming growth factor beta(1) (TGF-beta(1)), we considered it important to map the cis-acting regulatory element of the alpha1(I) collagen (col1a1) promoter involved in TNF-alpha responsiveness in hepatic stellate cells (HSC), to investigate the transcription factors that bind to it, and to establish possible mechanisms by which TNF-alpha down-regulates its expression. In this article, we show the presence of a functional TNF-alpha-responsive element (TaRE) in the -378 to -345 region of the col1a1 promoter. This element colocalizes with a previously reported TGF-beta(1)-responsive element. We further demonstrate that TNF-alpha induces nuclear translocation and binding of transcriptional complexes containing p20C/EBPbeta, p35C/EBPbeta, and C/EBPdelta to this sequence of the promoter. Transient overexpression of C/EBPdelta or p20C/EBPbeta, the natural dominant negative form of C/EBPbeta in HSC, down-regulated activity of a CAT reporter vector driven by -412 to +110 of the col1a1 promoter. Taken together, these data suggest that the -378 to -340 region of the col1a1 promoter is the site of convergence of different stimuli that ultimately modulate col1a1 gene transcription.

Authors+Show Affiliations

Division of Gastroenterology, Hepatology, and Nutrition, Marion Bessin Liver Research Center, and Departments of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10796884

Citation

Iraburu, M J., et al. "Tumor Necrosis Factor Alpha Down-regulates Expression of the alpha1(I) Collagen Gene in Rat Hepatic Stellate Cells Through a p20C/EBPbeta- and C/EBPdelta-dependent Mechanism." Hepatology (Baltimore, Md.), vol. 31, no. 5, 2000, pp. 1086-93.
Iraburu MJ, Domínguez-Rosales JA, Fontana L, et al. Tumor necrosis factor alpha down-regulates expression of the alpha1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPbeta- and C/EBPdelta-dependent mechanism. Hepatology. 2000;31(5):1086-93.
Iraburu, M. J., Domínguez-Rosales, J. A., Fontana, L., Auster, A., García-Trevijano, E. R., Covarrubias-Pinedo, A., Rivas-Estilla, A. M., Greenwel, P., & Rojkind, M. (2000). Tumor necrosis factor alpha down-regulates expression of the alpha1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPbeta- and C/EBPdelta-dependent mechanism. Hepatology (Baltimore, Md.), 31(5), 1086-93.
Iraburu MJ, et al. Tumor Necrosis Factor Alpha Down-regulates Expression of the alpha1(I) Collagen Gene in Rat Hepatic Stellate Cells Through a p20C/EBPbeta- and C/EBPdelta-dependent Mechanism. Hepatology. 2000;31(5):1086-93. PubMed PMID: 10796884.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor alpha down-regulates expression of the alpha1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPbeta- and C/EBPdelta-dependent mechanism. AU - Iraburu,M J, AU - Domínguez-Rosales,J A, AU - Fontana,L, AU - Auster,A, AU - García-Trevijano,E R, AU - Covarrubias-Pinedo,A, AU - Rivas-Estilla,A M, AU - Greenwel,P, AU - Rojkind,M, PY - 2000/5/5/pubmed PY - 2000/5/20/medline PY - 2000/5/5/entrez SP - 1086 EP - 93 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 31 IS - 5 N2 - Tumor necrosis factor alpha (TNF-alpha) is one of the key cytokines of the acute phase response and of many inflammatory processes. This cytokine has several antifibrogenic actions and down-regulates the expression of the type I collagen genes and induces the expression of metalloproteinases. Because TNF-alpha directly antagonizes some fibrogenic actions of transforming growth factor beta(1) (TGF-beta(1)), we considered it important to map the cis-acting regulatory element of the alpha1(I) collagen (col1a1) promoter involved in TNF-alpha responsiveness in hepatic stellate cells (HSC), to investigate the transcription factors that bind to it, and to establish possible mechanisms by which TNF-alpha down-regulates its expression. In this article, we show the presence of a functional TNF-alpha-responsive element (TaRE) in the -378 to -345 region of the col1a1 promoter. This element colocalizes with a previously reported TGF-beta(1)-responsive element. We further demonstrate that TNF-alpha induces nuclear translocation and binding of transcriptional complexes containing p20C/EBPbeta, p35C/EBPbeta, and C/EBPdelta to this sequence of the promoter. Transient overexpression of C/EBPdelta or p20C/EBPbeta, the natural dominant negative form of C/EBPbeta in HSC, down-regulated activity of a CAT reporter vector driven by -412 to +110 of the col1a1 promoter. Taken together, these data suggest that the -378 to -340 region of the col1a1 promoter is the site of convergence of different stimuli that ultimately modulate col1a1 gene transcription. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/10796884/Tumor_necrosis_factor_alpha_down_regulates_expression_of_the_alpha1_I__collagen_gene_in_rat_hepatic_stellate_cells_through_a_p20C/EBPbeta__and_C/EBPdelta_dependent_mechanism_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270913900001385 DB - PRIME DP - Unbound Medicine ER -