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LIVER AND BILIARY TRACT

TGF-1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70^S6k

¹Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461; ²Department of Biochemistry, Faculty of Medicine, Universidad Autónoma de Madrid, and Department of Experimental Endocrinology, Hospital Universitario Puerta de Hierro, Madrid, Spain 28029; ³Experimental Pathology and ⁴Chemistry Sections, Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC 20307; ⁵Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029; and ⁶Departments of Biochemistry and Molecular Biology and of Pathology, The George Washington University Medical Center, Washington, D.C. 20037

Submitted 17 June 2003 ; accepted in final form 26 May 2004

Transforming growth factor-1 (TGF-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 (MMP-13) mRNAs in hepatic stellate cells is reciprocally modulated. Because TGF-1 induces a transient elevation of 1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of MMP-13 mRNA during the downfall of the 1(I) collagen mRNA. In the present study, we report that TGF-1 induces a rapid decline in steady-state levels of MMP-13 mRNA at the time that it induces the expression of 1(I) collagen mRNA. This change in MMP-13 mRNA expression occurs within the first 6 h postcytokine administration and is accompanied by a twofold increase in gene transcription and a fivefold decrease in mRNA half-life. This is followed by increased expression of MMP-13 mRNA, which reaches maximal values by 48 h. Our results also show that this TGF-1-mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, phosphatidylinositol 3-kinase, AKT, and p70^S6k. Altogether, our data suggest that regulation of MMP-13 by TGF-1 is a complex process involving transcriptional and posttranscriptional mechanisms.

fibrosis; fibrogenesis; collagenase; collagen degradation

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