한빛사논문
- 조회2,933
Abstract
Junseong Park1,†, Wonseok Kang2,†, Seung-Wook Ryu1, Woo-Il Kim2, Dong-Yeop Chang2, Dong Ho Lee4, Do Youn Park5, Youn-Hee Choi6, Kyungsun Choi1, Eui-Cheol Shin2,3,*, Chulhee Choi1,2,3,*
1Department of Bio and Brain Engineering, Daejeon, 305-701, Republic of Korea
2Graduate School of Medical Science and Engineering, Daejeon, 305-701, Republic of Korea
3KAIST Institute for the BioCentury, KAIST, Daejeon, 305-701, Republic of Korea
4Department of Surgery, College of Medicine, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, 520-2, Republic of Korea
5Department of Pathology, Pusan National University Hospital and Pusan National University, Busan, 602-739, Republic of Korea
6Department of Physiology, Ewha Womans University School of Medicine, Seoul, 158-710, Republic of Korea
† These authors contributed equally to this work.
*Corresponding authors : Eui-Cheol Shin, Chulhee Choi
Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 305-701, Republic of Korea
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- α (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 IKK and 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 Bcl-xL, XIAP and c-FLIPL. Decreased levels of Bcl-xL, XIAP, and c-FLIP mRNA and protein were also observed in livers with chronic hepatitis C. Transfection with plasmids encoding each HCV protein revealed that core, NS4B, 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.)
논문정보
- Research article
- 2012년 03월 (BRIC 등록일 )
- 국내 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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