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Transforming growth factor β (TGF-β) stimulates reactive oxygen species (ROS) production in various cell types, which mediates many of the effects of TGF-β. The molecular mechanisms whereby TGF-β increases ROS production and ROS modulate the signaling processes of TGF-β, however, remain poorly defined. In this study, we show that TGF-β1 stimulates NADPH oxidase 4 (Nox4) expression and ROS generation in the nucleus of murine embryo fibroblasts (NIH3T3 cells). This is associated with an increase in protein thiol modification and inactivation of MAPK phosphatase 1 (MKP-1), a nuclear phosphatase. Furthermore, knockdown of MKP-1 using small interfering RNA enhances TGF-β1-induced phosphorylation of JNK and p38 as well as the expression of plasminogen activator inhibitor 1 (PAI-1), a TGF-β-responsive gene involved in the pathogenesis of many diseases. Knockdown of Nox4 with Nox4 …