Hepatitis C virus infection enhances TNFα-induced cell death via suppression of NF-κB
Hepatitis C virus infection enhances TNFα-induced cell death via suppression of NF-κB
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DOI：
10.1002/hep.25726
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发表时间：
2012-09-01
期刊：
影响因子：
13.5
通讯作者：
Choi, Chulhee
中科院分区：
文献类型：
--
作者：
Park, Junseong;Kang, Wonseok;Choi, Chulhee
丙型肝炎病毒（HCV）感染导致肝损伤和长期并发症，如肝硬化和肝细胞癌。HCV感染的肝损伤被认为是由宿主免疫反应引起的，而不是由病毒细胞病变作用引起的。肿瘤坏死因子- α (TNF-a)在丙型肝炎的炎症过程中起关键作用。TNF-a诱导细胞死亡，可通过核因子κ b (NF-？B)激活。我们研究了丙型肝炎病毒感染细胞中TNF-a信号转导的调控，并鉴定了对TNF-a诱导的细胞死亡敏感的丙型肝炎病毒蛋白。我们利用体外HCV感染模型（JFH-1，基因型2a）和Huh-7和Huh-7.5细胞研究了HCV感染对TNF-a信号转导的影响。我们发现tnf -a诱导的hcv感染细胞死亡显著增加。HCV感染降低了tnf -a诱导的I？B激酶（IKK）和NF-？(我吗?B)哪些是NF-的上游调控因子？B激活。HCV感染也抑制NF-？B和NF-?的表达b依赖性抗凋亡蛋白，如b细胞淋巴瘤特大号（Bcl-xL）、x -连锁凋亡抑制蛋白（XIAP）和长形细胞flice抑制蛋白（c-FLIP）。在慢性丙型肝炎患者肝脏中，Bcl-xL、XIAP和c-FLIP信使RNA和蛋白的水平也有所下降。转染编码每种HCV蛋白的质粒显示，核心蛋白、非结构蛋白（NS）4B和NS5B能减弱tnf -a诱导的NF-？B活化和增强tnf -a诱导的细胞死亡。结论：HCV感染通过抑制NF-？通过core、NS4B和NS5B的作用激活B。这一机制可能有助于HCV感染中免疫介导的肝损伤。(肝脏病学2012;56:831840)
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-a) plays a pivotal role in the inflammatory processes of hepatitis C. TNF-a induces cell death that can be ameliorated by nuclear factor kappaB (NF-?B) activation. We investigated the regulation of TNF-a signal transduction in HCV-infected cells and identified HCV proteins responsible for sensitization to TNF-a-induced cell death. We studied the effect of HCV infection on TNF-a 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-a-induced cell death significantly increased in HCV-infected cells. HCV infection diminished TNF-a-induced phosphorylation of I?B kinase (IKK) and inhibitor of NF-?B (I?B), which are upstream regulators of NF-?B activation. HCV infection also inhibited nuclear translocation of NF-?B and expression of NF-?B-dependent anti-apoptotic proteins, such as B-cell lymphomaextra 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-a-induced NF-?B activation and enhanced TNF-a-induced cell death. Conclusion: HCV infection enhances TNF-a-induced cell death by suppressing NF-?B activation through the action of core, NS4B, and NS5B. This mechanism may contribute to immune-mediated liver injury in HCV infection. (HEPATOLOGY 2012;56:831840)