Distinctive role of Stat3 and Erk-1/2 activation in mediating interferon-γ inhibition of TGF-β1 action

Interferon-γ (IFN-γ) is a multi-functional cytokine that elicits an anti-fibrotic activity in a variety of organs. In this study, we investigated the potential role and mechanism of IFN-γ in modulating the fibrogenic action of TGF-β1 in tubular epithelial cells. Incubation of human proximal tubular epithelial (HKC) cells with IFN-γ inhibited TGF-β1-mediated α-smooth muscle actin (α-SMA) expression. IFN-γ also abolished TGF-β1-induced fibronectin and plasminogen activator inhibitor-1 (PAI-1) expression. To explore the mechanisms by which INF-γ inhibits TGF-β1 action, the signaling pathways that are critical for mediating the anti-fibrotic activity of IFN-γ were studied. Stimulation of HKC cells with IFN-γ triggered a sustained activation of the extracellular signal-regulated protein kinase-1 and-2 (Erk-1/2) and signal transducer and activator of transcription-3 (Stat3). Blockade of Erk-1/2 activation with Mek1 inhibitor abolished the inhibitory effect of IFN-γ on αSMA expression, whereas inhibition of Stat3 activation had no influence. Constitutive activation of Erk-1/2 by ectopic expression of activated Mek1 mimicked IFN-γ and suppressed TGF-β1-mediated α-SMA expression. Interestingly, inhibition of Stat3 activation abolished the ability of IFN-γ to attenuate TGF-β1-mediated PAI-1 and fibronectin expression in HKC cells. These findings indicate that IFN-γ is capable of antagonizing the fibrogenic actions of TGF-β1 in renal tubular epithelial cells. The anti-fibrotic action of IFN-γ appears to be mediated through a coordinated activation of both Erk-1/2 and Stat3 signal pathways in a mutually independent fashion.