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Transforming growth factor-β (TGF-β) is a potent fibrogenic cytokine. The molecular mechanism underlying TGF-β fibrogenesis, however, has not been completely elucidated. In this study, we showed that TGFβ decreased the intracellular GSH content in murine embryo fibroblasts (NIH 3T3), which was followed by an increase in collagen I mRNA content and collagen protein production. Prevention of GSH depletion with N-acetylcysteine (NAC), GSH, or GSH ester abrogated TGF-β-stimulated collagen production, whereas a decrease in intracellular GSH content with l-buthionine-S,R-sulfoximine, an inhibitor of de novo GSH synthesis, enhanced TGF-β-stimulated collagen production. These results suggest that GSH depletion induced by TGF-β may mediate TGF-β-stimulated collagen production. In addition, we showed that TGF-β stimulated superoxide production and increased release of H₂O₂ from the cells …