Interferon-γ down-regulates expression of tumor necrosis factor-α converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats

Abstract

Interferon-γ (IFN-γ) is a potent cytokine that exerts antiproliferative and antifibrogenic effects on hepatic stellate cells (HSCs). Although therapeutic application of IFN-γ for chronic liver diseases is anticipated, the responses of activated HSCs to IFN-γ have not been fully elucidated. To seek unknown molecules and pathways that might be responsive to IFN-γ treatment in activated HSCs, we examined global protein expression profiles using two-dimensional gel electrophoresis combined with peptide mass fingerprint. We identified 76 increased and 59 decreased spots (>3-fold increase or decrease, total 135 spots). Database analysis suggested that the following four pathways were involved in alteration of HSCs toward a quiescent phenotype in response to IFN-γ: i) down-regulation of the TGF-β and PDGF signaling pathways; ii) reorganization of intermediate filaments; iii) up-regulation of fatty acid metabolism; iv) decreased expression of TNF-α converting enzyme (TACE)/a disintegrin and metalloproteinase 17 (ADAM17), which is responsible for shedding of the proinflammatory cytokine TNF-α. We confirmed down-regulation of both ADAM17 expression and soluble TNF-α secretion by Western blotting and real-time PCR. TNF-α mRNA/protein expression was not altered by IFN-γ treatment. Our data suggest that IFN-γ stimulation suppresses the activated phenotype of HSCs in vitro through multiple pathways. Of these pathways, down-regulation of ADAM17 expression may play a role in blocking the auto-activation mechanism of cultured HSCs through activation of the TNF-α signaling and shedding pathways.