Double-stranded RNA-induced interferon-beta and inflammatory cytokine production modulated by hepatitis C virus serine proteases derived from patients with hepatic diseases
Double-stranded RNA-induced interferon-beta and inflammatory cytokine production modulated by hepatitis C virus serine proteases derived from patients with hepatic diseases
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DOI：
10.1007/s00705-009-0375-z
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发表时间：
2009-05-01
影响因子：
2.7
通讯作者：
Kato, Nobuyuki
中科院分区：
文献类型：
--
作者：
Dansako, Hiromichi;Ikeda, Masanori;Kato, Nobuyuki
我们以前证明丙型肝炎病毒（HCV）丝氨酸蛋白酶NS 3 -4A不能切割TRIF（Toll样受体3的衔接蛋白），导致缺乏对TRIF介导的途径的抑制，而NS 3 -4A切割Cardif（视黄酸诱导基因I或黑素瘤分化相关基因-5的衔接蛋白），导致非肿瘤性人肝细胞PH 5CH 8细胞中Cardif介导的途径中断。为了阐明这些观察结果，我们检查了NS 3 -4A在PH 5CH 8细胞、基因组长度的HCV RNA复制O细胞和HCV感染的细胞中对TRIF的切割潜力，并且我们证明了NS 3 -4A缺乏切割内源性TRIF的能力，无论来自不同肝病阶段患者的HCV毒株如何。此外，我们证明了通过TRIF介导的途径激活NF-κ B产生的炎性细胞因子也不受NS 3 -4A抑制。这些结果表明，NS 3 -4A对抗病毒信号通路的抑制作用仅限于人肝细胞中Cardif介导的通路。
We previously demonstrated that hepatitis C virus (HCV) serine protease NS3-4A was unable to cleave TRIF (adaptor protein of Toll-like receptor 3), resulting in a lack of suppression of the TRIF-mediated pathway, whereas NS3-4A cleaved Cardif (adaptor protein of retinoic acid-inducible gene I or melanoma differentiation-associated gene-5), resulting in an interruption of the Cardif-mediated pathway in non-neoplastic human hepatocyte PH5CH8 cells. To elucidate these observations, we examined the cleavage potential of NS3-4A for TRIF in PH5CH8 cells, genome-length HCV RNA-replicating O cells, and HCV-infected cells, and we demonstrated that NS3-4A lacked the ability to cleave endogenous TRIF, regardless of HCV strains derived from patients with different stages of hepatic disease. Furthermore, we demonstrated that inflammatory cytokine production by NF-kappa B activation via the TRIF-mediated pathway also remained unsuppressed by NS3-4A. These results suggest that the inhibitory effects of NS3-4A on antiviral signaling pathways are limited to the Cardif-mediated pathway in human hepatocytes.