Critical role of CREBH‐mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells

摘要

Mechanisms of hepatic fibrogenesis induced by hepatitis C virus (HCV), one of the leading causes of liver fibrosis, are not fully understood. We studied transcriptional upregulation of transforming growth factor ?(TGF?, especially TGF?, which is mediated by activation of liverenriched transcription factor cAMPresponsive elementbinding protein, hepatocyte specific (CREBH) triggered by HCV infection and its functional significance for induction of profibrogenic phenotypes by interaction of HCVinfected cells with hepatic stellate cells (HSCs). Compared to TGF?, expression of TGF? mRNA was induced faster and to a higher level upon HCV infection. Serum TGF? levels in hepatitis C patients were higher compared to those in healthy individuals and were positively correlated with hepatic fibrosis stages F0F2. TGF? promoter activity was decreased and increased, respectively, by silencing and overexpression of CREBH. CREBH recognition sites were identified in the TGF? promoter. CREBH binding to the promoter and its increase in cells expressing HCV CoreNS2 were shown by gel mobility shift and chromatin immunoprecipitation, respectively. The active form of CREBH was detectable in HCVinfected chimeric mice with human livers and cells expressing HCV proteins. Involvement of CREBH in HCVinduced fibrogenic response was further demonstrated in the CREBH nullmutant mouse model. Fibrogenic phenotypes were assessed using cocultures of HCVinfected cells and HSCs. Expressions of fibrogenic factors and TGF? increasing in the cocultures was prevented by TGF? or CREBH silencing.Conclusion : CREBH was identified as a key positive regulator of TGF? transcription in HCVinfected cells. TGF? released from infected cells potentially contributes to crossinduction of TGF?in an autocrine manner through its own signaling pathway, leading to an increase in fibrogenic responses in adjacent HSCs. (Hepatology 2017;66:14301443).