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Transforming Growth Factor b 1 Induces the Expression of a 1(I) Procollagen mRNA by a Hydrogen Peroxide-C/EBP b -Dependent Mechanism in Rat Hepatic Stellate Cells

Oxidative stress plays a key role in liver fibrosis. Both inflammatory cells and activated Kupffer cells produce H 2 O 2 , 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 b (TGF- b ), and this cytokine enhances collagen production by cultured HSC. However, the possible link between oxidative stress and the molecular mechanisms by which TGF- b induces collagen gene expression in HSC remains to be elucidated. To address this question, we investigated whether H 2 O 2 is a mediator of TGF- b -elicited a 1(I) collagen gene ( col1a1 ) up-regulation. We demonstrated that TGF- b induces the accumulation of H 2 O 2 , and that this oxidant is, in turn, directly involved in up-regulating the expression of the col1a1 gene. While the addition of H 2 O 2 to HSC induced the expression of a 1(I) procollagen mRNA, catalase, an H 2 O 2 enzyme scavenger, abrogated TGF- b -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 ( 2 370 to 2 344) essential for TGF- b responsiveness. We further showed that TGF- b induced the activation and binding of a C/EBP