Induction of high-molecular-weight (HMW) tumor necrosis factor(TNF) alpha by hepatitis C virus (HCV) non-structural protein 3 (NS3) in liver cells is AP-1 and NF-κB-dependent activation
Induction of high-molecular-weight (HMW) tumor necrosis factor(TNF) alpha by hepatitis C virus (HCV) non-structural protein 3 (NS3) in liver cells is AP-1 and NF-κB-dependent activation
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DOI：
10.1016/j.cellsig.2006.07.002
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发表时间：
2007-02-01
影响因子：
4.8
通讯作者：
Abdel-Kader, Ola
中科院分区：
文献类型：
--
作者：
Hassan, Mohamed;Selimovic, Denis;Abdel-Kader, Ola
丙型肝炎病毒感染患者的慢性感染与血清和肝间炎性细胞因子的产生有关，其中包括肿瘤坏死因子-α。在这项研究中，我们描述了丙型肝炎病毒诱导人肝细胞系HepG2和Huh7合成肿瘤坏死因子-α的部分机制。瞬时转染丙型肝炎病毒全长c DNA的HepG2细胞表达高分子量(HMW)的肿瘤坏死因子-αmRNAs，而对照组细胞中没有表达。此外，在HepG2和Huh7中严格调控的丙型肝炎病毒NS3的表达被发现诱导HMW mRNAs的表达，随后产生具有生物活性的肿瘤坏死因子-α。有趣的是，在HepG2-NS3或Huh7-NS3中，NS3蛋白的表达导致了NF-αB抑制物(IαB)的激酶(ikk-α)的激活，并增强了核转录因子NF-kappa B的DNA结合活性。在HepG2-NS3或Huh7-NS3细胞中，用NF-kappa B的抑制剂处理后，抑制了TNF-αmRNAs的转录，进而抑制了TNF-α的产生，提示NF-kappa B在调控NS3-TNF-a表达方面具有重要意义。有趣的是，在肝脏和非肝细胞中，荧光素酶检测的数据表明，NS3蛋白通过激活AP-1和NF-kappa B来调节肿瘤坏死因子-α启动子。我们的数据表明，丙型肝炎病毒诱导的肝内肿瘤坏死因子-α的产生是由丙型肝炎病毒NS3转录上调的。因此，在急性和慢性丙型肝炎期间，丙型肝炎病毒NS3可能在诱导肝内炎症过程中起到潜在作用。(C)2006年爱思唯尔公司。保留所有权利。
Chronic infection of hepatitis C virus (HCV)-infected patients is associated with the production of serum and interhepatic inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha). In this study, we delineated part of the mechanism whereby HCV induces the synthesis of TNF-alpha in human liver cell lines HepG2 and Huh7. HepG2 transiently transfected with the full-length HCV cDNA expressed high-molecular-weight (HMW) TNF-alpha mRNAs, which were absent in the control cells. In addition tightly regulated expression of HCV NS3 in both HepG2 and Huh7 was found to induce the expression of HMW mRNAs and subsequently the production of biologically active TNF-alpha. Interestingly, the expression of NS3 protein in HepG2-NS3 or in Huh7-NS3 resulted in the activation of kinase (IKK-alpha) of NF-alpha B inhibitor (I alpha B) and in the enhancement of the DNA-binding activity of the nuclear transcription factor NF-kappa B. The inhibition of the transcription of TNF-alpha mRNAs and subsequently TNF-alpha production following the treatment of HepG2-NS3 or Huh7-NS3 transfectants with the inhibitor of NF-kappa B, Bay 11-7082, suggesting the importance of NF-kappa B for the regulation of NS3-mediated TNF-a expression in HepG2 and HeLa cells. Interestingly, data obtained from luciferase assays, in liver and in non-liver cells showed the contribution of NS3 protein in the regulation of TNF-alpha promoter through the activation of AP-1 and NF-kappa B. Our data indicate that the intrahepatic TNF-alpha production induced by HCV is transcriptionally up-regulated by HCV NS3. Therefore, HCV NS3 may have a potential role in the induction of intrahepatic inflammatory processes that occur during acute and chronic hepatitis C. (c) 2006 Elsevier Inc. All rights reserved.