Transforming Growth Factor β1 Induces the Expression of α1(I) Procollagen Mrna by A Hydrogen Peroxide–C/Ebpβ–Dependent Mechanism in Rat Hepatic Stellate Cells

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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 β (TGF–β), and this cytokine enhances collagen production by cultured HSC. However, the possible link between oxidative stress and the molecular mechanisms by which TGF–β induces collagen gene expression in HSC remains to be elucidated. To address this question, we investigated whether H2O2 is a mediator of TGF–β–elicited α1(I) collagen gene (col1a1) up–regulation. We demonstrated that TGF–β 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 α1(I) procollagen mRNA, catalase, an H2O2 enzyme scavenger, abrogated TGF–β–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–β responsiveness. We further showed that TGF–β induced the activation and binding of a C/EBPβ–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–β–mediated accumulation of H2O2 and the up–regulation of col1a1 gene in HSC.
Funding Information
  • Fundación Ramón Areces, Madrid, Spain (to L.F.) (RO1 AA09231)
  • National Institutes of Health (RO1 AA10541)

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