PMID- 22430873
OWN - NLM
STAT- MEDLINE
DCOM- 20121030
LR  - 20160729
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 56
IP  - 3
DP  - 2012 Sep
TI  - Hepatitis C virus infection enhances TNFalpha-induced cell death via suppression of 
      NF-kappaB.
PG  - 831-40
LID - 10.1002/hep.25726 [doi]
AB  - 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-alpha) plays a pivotal role in 
      the inflammatory processes of hepatitis C. TNF-alpha induces cell death that can be 
      ameliorated by nuclear factor kappaB (NF-kappaB) activation. We investigated the 
      regulation of TNF-alpha signal transduction in HCV-infected cells and identified HCV 
      proteins responsible for sensitization to TNF-alpha-induced cell death. We studied 
      the effect of HCV infection on TNF-alpha 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-alpha-induced cell death significantly increased in HCV-infected cells. HCV 
      infection diminished TNF-alpha-induced phosphorylation of IkappaB kinase (IKK) and 
      inhibitor of NF-kappaB (IkappaB), which are upstream regulators of NF-kappaB activation. HCV 
      infection also inhibited nuclear translocation of NF-kappaB and expression of 
      NF-kappaB-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-alpha-induced NF-kappaB 
      activation and enhanced TNF-alpha-induced cell death. CONCLUSION: HCV infection 
      enhances TNF-alpha-induced cell death by suppressing NF-kappaB activation through the 
      action of core, NS4B, and NS5B. This mechanism may contribute to immune-mediated 
      liver injury in HCV infection.
CI  - Copyright (c) 2012 American Association for the Study of Liver Diseases.
FAU - Park, Junseong
AU  - Park J
AD  - Department of Bio and Brain Engineering, Korea Advanced Institute of Science and 
      Technology, Daejeon, Republic of Korea.
FAU - Kang, Wonseok
AU  - Kang W
FAU - Ryu, Seung-Wook
AU  - Ryu SW
FAU - Kim, Woo-Il
AU  - Kim WI
FAU - Chang, Dong-Yeop
AU  - Chang DY
FAU - Lee, Dong Ho
AU  - Lee DH
FAU - Park, Do Youn
AU  - Park DY
FAU - Choi, Youn-Hee
AU  - Choi YH
FAU - Choi, Kyungsun
AU  - Choi K
FAU - Shin, Eui-Cheol
AU  - Shin EC
FAU - Choi, Chulhee
AU  - Choi C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120726
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Cell Death/*physiology
MH  - Cells, Cultured
MH  - Hepatitis C/*immunology
MH  - Humans
MH  - NF-kappa B/*physiology
MH  - Tumor Necrosis Factor-alpha/*physiology
EDAT- 2012/03/21 06:00
MHDA- 2012/10/31 06:00
CRDT- 2012/03/21 06:00
PHST- 2011/10/26 00:00 [received]
PHST- 2012/03/06 00:00 [accepted]
PHST- 2012/03/21 06:00 [entrez]
PHST- 2012/03/21 06:00 [pubmed]
PHST- 2012/10/31 06:00 [medline]
AID - 10.1002/hep.25726 [doi]
PST - ppublish
SO  - Hepatology. 2012 Sep;56(3):831-40. doi: 10.1002/hep.25726. Epub 2012 Jul 26.