IFN-γ abrogates profibrogenic TGF-β signaling in liver by targeting expression of inhibitory and receptor Smads

Background/Aims:In a randomized open-labeled multicenter trial with patients suffering from chronic HBV infection, we recently identified a benefit of 9-month IFN-gamma treatment resulting in decreased fibrosis scores and a reduced number of alpha-smooth muscle actin-positive hepatic stellate cells (HSCs). Approaches opposing profibrogenic activities of TGF-beta may be amenable in chronic liver disease. According to experimental models, IFN-gamma counteracts several TGF-beta effects. Methods: The crosstalk of IFN-gamma and TGF-beta signaling relevant for fibrogenesis was investigated in primary cultured rat HSCs and a cell line representing activated HSCs. Results: In vitro studies with HSCs demonstrate that TGF-beta-dependent activation of (CAGA)(9)-MLP-Luc, a Smad3/4 responsive reporter construct, was significantly decreased by IFN-gamma, indicating a TGF-beta antagonizing function. IFN-gamma induced the activity of the Smad7 promoter and Smad7 protein expression via STAT-1 signaling. In contrast to TGF-beta, IFN-gamma was able to induce Smad7 expression in activated HSCs providing increased protein levels for at least 12 h. In addition, expression of Smad2/3 was reduced by IFN-gamma and activation of Smads2/3 was abrogated. Conclusions: IFN-gamma displays antifibrotic effects in liver cells via STAT-1 phosphorylation, upregulation of Smad7 expression and impaired TGF-beta signaling. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.