title: Hepatitis C virus infection enhances TNFα-induced cell death via suppression of NF-κB.
abstract: Hepatitis C virus (HCV) infection results in liver injury and long-term complications, such as liver cirrhosis and hepatocellular carcinoma. Liver injury in HCV infection is believed to be caused by host immune responses, not by viral cytopathic effects. Tumor necrosis factor-alpha (TNF-α) plays a pivotal role in the inflammatory processes of hepatitis C. TNF-α induces cell death that can be ameliorated by nuclear factor kappaB (NF-κB) activation. We investigated the regulation of TNF-α signal transduction in HCV-infected cells and identified HCV proteins responsible for sensitization to TNF-α-induced cell death. We studied the effect of HCV infection on TNF-α signal transduction using an in vitro HCV infection model (JFH-1, genotype 2a) with Huh-7 and Huh-7.5 cells. We found that TNF-α-induced cell death significantly increased in HCV-infected cells. HCV infection diminished TNF-α-induced phosphorylation of IκB kinase (IKK) and inhibitor of NF-κB (IκB), which are upstream regulators of NF-κB activation. HCV infection also inhibited nuclear translocation of NF-κB and expression of NF-κB-dependent anti-apoptotic proteins, such as B-cell lymphoma--extra large (Bcl-xL), X-linked inhibitor of apoptosis protein (XIAP), and the long form of cellular-FLICE inhibitory protein (c-FLIP). Decreased levels of Bcl-xL, XIAP, and c-FLIP messenger RNA and protein were also observed in livers with chronic hepatitis C. Transfection with plasmids encoding each HCV protein revealed that core, nonstructural protein (NS)4B, and NS5B attenuated TNF-α-induced NF-κB activation and enhanced TNF-α-induced cell death.
  
  
  CONCLUSIONS
  HCV infection enhances TNF-α-induced cell death by suppressing NF-κB activation through the action of core, NS4B, and NS5B. This mechanism may contribute to immune-mediated liver injury in HCV infection.
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Junseong
authors.initials: J
authors.lastname: Park
authors.forename: Wonseok
authors.initials: W
authors.lastname: Kang
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Ryu
authors.forename: Woo-Il
authors.initials: WI
authors.lastname: Kim
authors.forename: Dong-Yeop
authors.initials: DY
authors.lastname: Chang
authors.forename: Dong Ho
authors.initials: DH
authors.lastname: Lee
authors.forename: Do Youn
authors.initials: DY
authors.lastname: Park
authors.forename: Youn-Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: Kyungsun
authors.initials: K
authors.lastname: Choi
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
mesh_terms: D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha