Molecular mechanism of inflammatory cytokine induction by hepatitis viruses

肝炎病毒会导致持续性感染、慢性肝炎、肝硬变和肝细胞癌。本研究探讨了乙型肝炎、丙型肝炎病毒和三角洲病毒(分别为乙肝病毒、丙型肝炎病毒和丁型肝炎病毒)蛋白对肝细胞功能的影响，特别是对炎性细胞因子的诱导。在15种病毒蛋白中，丙型肝炎病毒核心蛋白激活了核因子-KB、AP-1、MAP激酶和P53相关的信号通路。丙型肝炎病毒核心蛋白通过激活核因子-KB上调IL-16和-8启动子的表达，通过激活p53上调p21的表达。核心蛋白通过IKKβ和肿瘤坏死因子受体相关因子(TRAF)激活NF-KB途径，并通过增强DNA结合亲和力和转录能力增强P53的功能。核心蛋白可能通过激活核因子-KB、AP-1和MAP激酶相关的信号通路，直接促进细胞增殖和诱导炎症反应。另一方面，核心蛋白可以增强…P53的作用更强。这些相反的功能可能导致微妙地平衡感染了HCV的肝细胞的增殖。在慢性肝炎中，细胞凋亡与肝脏的炎症有关。在表达丙型肝炎病毒核心蛋白的细胞中，半胱氨酸天冬氨酸氨基转移酶3的激活受到抑制，而bclx_L的表达增加。核心蛋白通过激活MAP激酶级联，促进Bclx_L的表达，从而在线粒体水平上抑制Fas诱导的细胞凋亡信号。核心蛋白介导的Bclx_L的诱导可能是其抑制细胞凋亡的机制之一，这可能是HCVNS4A和NS4B蛋白抑制细胞翻译过程(翻译关闭)的机制之一。这一功能可能参与了丙型肝炎病毒的感染，并帮助其在宿主细胞中存活。除丙型肝炎病毒蛋白外，HDV大抗原还可激活SRF相关途径，并与HBx蛋白协同激活SRE。综上所述，肝炎病毒蛋白可影响细胞内信号通路，诱导炎性细胞因子，从而引起肝脏炎症。较少

Hepatitis viruses cause persistent infection, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In this study, the influence of hepatitis B, C, and delta virus (HBV, HCV, and HDV, respectively) proteins on the function of hepatocyte, especially the induction of inflammatory cytokines, was investigated. Among 15 viral proteins, HCV core protein activated NF-_KB, AP-1, MAP kinase, and P53-associated signaling pathways. HCV core protein upregulated interleukin-16 and -8 promoters through NF-_KB activation, and increased p21 expression through p53 activation. The core protein activated NF-_KB pathway through IKKβand tumor necrosis factor receptor-associated factor (TRAF), and enhanced p53 function through augmentation of DNA-binding affinity and transcriptional ability. The core protein may directly promote cell proliferation and induce an inflammatory reaction by activating NF-_KB, AP-1, and MAP kinase-assosiated signaling pathways. On the other hand, the core protein could enha … More nce p53 function. These opposing functions may result in exquisitely balancing the proliferation of hepatocytes infected with HCV.Apoptosis is related to inflammation of the liver in chronic hepatitis. In HCV core protein-expressing cell, activation of caspase 3 was inhibited and Bcl-x_L expression was increased. The core protein enhances the Bcl-x_L expression through activating MAP kinase cascade, and thus inhibits apoptotic signal induced by Fas at the mitochondria level. Core protein-mediated Bcl-x_L induction may be one of the mechanisms underlying its inhibition of apoptosis, which might contribute to the pathogenesis of HCV.HCV NS4A and NS4B proteins generally suppressed cellular translation process (translational shutoff). This function may be involved in HCV infection and help its survival in host cells. In addition to HCV proteins, HDV large antigen activated SRF-associated pathway and synergistically activated SRE with HBx protein.In summary, hepatitis virus proteins may influence intracellular signaling pathways, induce inflammatory cytokines, and thus cause inflammation of the liver. Less