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Am J Physiol Gastrointest Liver Physiol (July 8, 2004). doi:10.1152/ajpgi.00264.2003
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Submitted on June 17, 2003
Accepted on May 26, 2004

TGF-{beta}1 Modulates Matrix Metalloproteinase-13 expression in Hepatic Stellate Cells by Complex Mechanisms Involving p38MAPK, PI3K, AKT and p70S6K

Carmen G. Lechuga1, Zamira H. Hernandez-Nazara2, Jose-Alfredo Dominguez Rosales2, Elena R. Morris3, Ana Rosa Rincon4, Ana Maria Rivas-Estilla5, Andres Esteban-Gamboa6, and Marcos Rojkind7*

1 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Biochemistry, Faculty of Medicine and Department of Experimental Endocrinology, Universidad Autonoma de Madrid and Hospital Universitario Puerta de Hierro, Madrid, Madrid, Spain
2 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA; Experimental Pathology Section, Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC, USA
3 Chemistry Section, Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC, USA
4 Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY, USA
5 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
6 Department of Biochemistry, Faculty of Medicine and Department of Experimental Endocrinology, Universidad Autonoma de Madrid and Hospital Universitario Puerta de Hierro, Madrid, Madrid, Spain
7 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA; Experimental Pathology Section, Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC, USA; Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC, USA

* To whom correspondence should be addressed. E-mail: bcmmmr{at}gwumc.edu.

Transforming growth factor-{beta}1 the main cytokine involved in liver fibrogenesis induces expression of the type I collagen genes in hepatic stellate cells by a transcriptional mechanism which is hydrogen peroxide- and de novo protein synthesis-dependent. Our recent studies have revealed that expression of type I collagen and matrix metalloproteinase-13 mRNAs in hepatic stellate cells is reciprocally modulated. Because transforming growth factor-{beta}1 induces a transient elevation of {alpha}1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of matrix metalloproteinase-13 mRNA during the downfall of the {alpha}1(I) collagen mRNA. In this communication we report that TGF-{beta}1 induces a rapid decline in steady-state levels of matrix metalloproteinase-13 mRNA at the time that it induces the expression of {alpha}1(I) collagen mRNA. This change in matrix metalloproteinase-13 mRNA expression occurs within the first 6 hours post-cytokine administration and is accompanied by a two-fold increase in gene transcription and a five-fold decrease in mRNA half-life. This is followed by increased expression of matrix metalloproteinase-13 mRNA that reaches maximal values by 48 hours. Our results also show that this transforming growth factor{beta}1- mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, PI3K, AKT and p70S6K. Altogether, our data suggest that regulation of MMP-13 by TGF-{beta}1 is a complex process involving transcriptional and posttranscriptional mechanisms.




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