Hepatitis C virus infection enhances TNFα-induced cell death via suppression of NF-κB

Authors

  • Junseong Park,

    1. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
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    • These authors contributed equally to this work.

  • Wonseok Kang,

    1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea KAIST Daejeon, Republic of Korea
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    • These authors contributed equally to this work.

  • Seung-Wook Ryu,

    1. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
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  • Woo-Il Kim,

    1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea KAIST Daejeon, Republic of Korea
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  • Dong-Yeop Chang,

    1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea KAIST Daejeon, Republic of Korea
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  • Dong Ho Lee,

    1. Department of Surgery, College of Medicine, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Republic of Korea
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  • Do Youn Park,

    1. Department of Pathology, Pusan National University Hospital and Pusan National University, Busan, Republic of Korea
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  • Youn-Hee Choi,

    1. Department of Physiology, Ewha Womans University School of Medicine, Seoul, Republic of Korea
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  • Kyungsun Choi,

    1. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
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  • Eui-Cheol Shin,

    Corresponding author
    1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea KAIST Daejeon, Republic of Korea
    2. KAIST Institute for the BioCentury, KAIST, Daejeon, Republic of Korea
    • Eui-Cheol Shin, Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea===

      Chulhee Choi, Department of Bio and Brain Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea===

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  • Chulhee Choi

    Corresponding author
    1. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea KAIST Daejeon, Republic of Korea
    3. KAIST Institute for the BioCentury, KAIST, Daejeon, Republic of Korea
    • Eui-Cheol Shin, Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea===

      Chulhee Choi, Department of Bio and Brain Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea===

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    • fax: +82-42-350-4380


  • Potential conflict of interest: Nothing to report.

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. Conclusion: 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. (HEPATOLOGY 2012;56:831–840)

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