IFN-γ Abrogates Profibrogenic TGF-β Signaling in the Liver by Targeting the Expression of Pathway-Restricted and Inhibitory Smads

In chronic liver disease, approaches opposing profibrogenic activities of TGF-β may be amenable. According to experimental models IFN-γ counteracts several TGF-β effects. Here, the impact of IFN-γ on hepatic fibrosis in patients with chronic hepatitis B viral (HBV) infection with emphasis on IFN-γ signaling during activation of hepatic stellate cells (HSC) was investigated. In a randomized open-label multicenter trial 83 chronically HBV infected patients were included, 54 patients received a nine-month IFN-γ treatment, whereas 29 patients served as controls. Histology and serum indices displayed a beneficial outcome in the IFN-γ treatment group. As consequence of IFN-γ application, fibrosis scores decreased significantly according to the modified Chevallier criterion, as were the number of smooth muscle actin-positive HSC. In HSC TGF-β-dependent activation of (CAGA)9-MLP-Luc, a highly sensitive TGF-β reporter construct, was significantly decreased by IFN-γ indicating a TGF-β antagonizing function. Transfection of a Smad7 promoter construct and Smad7 immunoblotting indicated that IFN-γ is able to induce Smad7 transcription and protein expression. Furthermore, our data reveal that IFN-γ signaling in HSC is mediated via STAT–1. Immunostainings of liver biopsies indicated that disease-dependent TGF-β signaling is abrogated by IFN-γ-treatment. Nuclear phospho-Smad2 staining was predominant in damaged tissue and absent after IFN-γ treatmen, whereas strong cytoplasmatic Smad7 staining was only observed after IFN-γ application. In summary, IFN-γ displays beneficial anti-fibrotic effects in patients with chronic HBV infection via STAT–1 phosphorylation, upregulation of Smad7 expression and impaired TGF-β signaling.

Key words

fibrosis - hepatic stellate cells - hepatitis b