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

Title
Hepatitis C virus infection enhances TNFα-induced cell death via suppression of NF-κB
Authors
Park J.Kang W.Ryu S.-W.Kim W.-I.Chang D.-Y.Lee D.H.Park D.Y.Choi Y.-H.Choi K.Shin E.-C.Choi C.
Ewha Authors
최윤희
SCOPUS Author ID
최윤희scopus
Issue Date
2012
Journal Title
Hepatology
ISSN
0270-9139JCR Link
Citation
vol. 56, no. 3, pp. 831 - 840
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. © 2012 American Association for the Study of Liver Diseases.
DOI
10.1002/hep.25726
Appears in Collections:
의학전문대학원 > 의학과 > Journal papers
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