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Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells.
Hepatology. 1999 Mar; 29(3):960-70.Hep

Abstract

Oxidative stress plays a key role in liver fibrosis. Both inflammatory cells and activated Kupffer cells produce H2O2, an oxidant involved in the activation of hepatic stellate cells (HSC). Increased production of reactive oxygen intermediates (ROIs) in fibrotic livers is associated in part with the up-regulation of transforming growth factor beta (TGF-beta), and this cytokine enhances collagen production by cultured HSC. However, the possible link between oxidative stress and the molecular mechanisms by which TGF-beta induces collagen gene expression in HSC remains to be elucidated. To address this question, we investigated whether H2O2 is a mediator of TGF-beta-elicited alpha1(I) collagen gene (col1a1) up-regulation. We demonstrated that TGF-beta induces the accumulation of H2O2, and that this oxidant is, in turn, directly involved in up-regulating the expression of the col1a1 gene. While the addition of H2O2 to HSC induced the expression of alpha1(I) procollagen mRNA, catalase, an H2O2 enzyme scavenger, abrogated TGF-beta-mediated col1a1 gene up-regulation. We transfected HSC with chimeric plasmids driven by different segments of the mouse col1a1 promoter and mapped a cis-acting element (-370 to -344) essential for TGF-beta responsiveness. We further showed that TGF-beta induced the activation and binding of a C/EBPbeta-containing transcriptional complex to this sequence, an effect that was also mimicked by the addition of H2O2. Taken together, these data demonstrate a direct connection between TGF-beta-mediated accumulation of H2O2 and the up-regulation of col1a1 gene in HSC.

Authors+Show Affiliations

Division of Gastroenterology, Hepatology, and Nutrition, Marion Bessin Liver Research Center, 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 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

10051504

Citation

García-Trevijano, E R., et al. "Transforming Growth Factor Beta1 Induces the Expression of alpha1(I) Procollagen mRNA By a Hydrogen peroxide-C/EBPbeta-dependent Mechanism in Rat Hepatic Stellate Cells." Hepatology (Baltimore, Md.), vol. 29, no. 3, 1999, pp. 960-70.
García-Trevijano ER, Iraburu MJ, Fontana L, et al. Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells. Hepatology. 1999;29(3):960-70.
García-Trevijano, E. R., Iraburu, M. J., Fontana, L., Domínguez-Rosales, J. A., Auster, A., Covarrubias-Pinedo, A., & Rojkind, M. (1999). Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells. Hepatology (Baltimore, Md.), 29(3), 960-70.
García-Trevijano ER, et al. Transforming Growth Factor Beta1 Induces the Expression of alpha1(I) Procollagen mRNA By a Hydrogen peroxide-C/EBPbeta-dependent Mechanism in Rat Hepatic Stellate Cells. Hepatology. 1999;29(3):960-70. PubMed PMID: 10051504.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells. AU - García-Trevijano,E R, AU - Iraburu,M J, AU - Fontana,L, AU - Domínguez-Rosales,J A, AU - Auster,A, AU - Covarrubias-Pinedo,A, AU - Rojkind,M, PY - 1999/3/3/pubmed PY - 1999/3/3/medline PY - 1999/3/3/entrez SP - 960 EP - 70 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 29 IS - 3 N2 - Oxidative stress plays a key role in liver fibrosis. Both inflammatory cells and activated Kupffer cells produce H2O2, an oxidant involved in the activation of hepatic stellate cells (HSC). Increased production of reactive oxygen intermediates (ROIs) in fibrotic livers is associated in part with the up-regulation of transforming growth factor beta (TGF-beta), and this cytokine enhances collagen production by cultured HSC. However, the possible link between oxidative stress and the molecular mechanisms by which TGF-beta induces collagen gene expression in HSC remains to be elucidated. To address this question, we investigated whether H2O2 is a mediator of TGF-beta-elicited alpha1(I) collagen gene (col1a1) up-regulation. We demonstrated that TGF-beta induces the accumulation of H2O2, and that this oxidant is, in turn, directly involved in up-regulating the expression of the col1a1 gene. While the addition of H2O2 to HSC induced the expression of alpha1(I) procollagen mRNA, catalase, an H2O2 enzyme scavenger, abrogated TGF-beta-mediated col1a1 gene up-regulation. We transfected HSC with chimeric plasmids driven by different segments of the mouse col1a1 promoter and mapped a cis-acting element (-370 to -344) essential for TGF-beta responsiveness. We further showed that TGF-beta induced the activation and binding of a C/EBPbeta-containing transcriptional complex to this sequence, an effect that was also mimicked by the addition of H2O2. Taken together, these data demonstrate a direct connection between TGF-beta-mediated accumulation of H2O2 and the up-regulation of col1a1 gene in HSC. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/10051504/Transforming_growth_factor_beta1_induces_the_expression_of_alpha1_I__procollagen_mRNA_by_a_hydrogen_peroxide_C/EBPbeta_dependent_mechanism_in_rat_hepatic_stellate_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270913999001445 DB - PRIME DP - Unbound Medicine ER -