Extracellular Hepatitis C Virus Core Protein Activates STAT3 in Human Monocytes/Macrophages/Dendritic Cells via an IL-6 Autocrine Pathway
Extracellular Hepatitis C Virus Core Protein Activates STAT3 in Human Monocytes/Macrophages/Dendritic Cells via an IL-6 Autocrine Pathway
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DOI：
10.1074/jbc.m110.217653
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发表时间：
2011-03-25
影响因子：
4.8
通讯作者：
Hahn, Young S.
中科院分区：
文献类型：
--
作者：
Tacke, Robert S.;Tosello-Trampont, Annie;Hahn, Young S.
丙型肝炎病毒（HCV）感染是建立持续感染，导致慢性肝病和肝细胞癌的发展非常有效。据报道，IFN-γ产生减少的T细胞应答受损与持续的HCV感染有关。细胞外HCV核心是已知通过其对抗原呈递细胞（APC）的促炎反应的激活和诱导的抑制作用引起HCV诱导的T细胞损伤的病毒因子。STAT蛋白的激活已被报道调节炎症反应和APC的分化。为了进一步表征细胞外HCV核心调节APC功能的分子基础，我们检测了细胞外HCV核心激活STAT家族成员（STAT 1、-2、-3、-5和-6）的能力。在这项研究中，我们报告了STAT 3对人单核细胞，巨噬细胞和树突状细胞的激活后，与细胞外的HCV核心，以及治疗与gC 1 qR激动性单克隆抗体。重要的是，HCV核心诱导的STAT 3活化依赖于PI 3 K/Akt通路的活化。此外，多功能细胞因子IL-6的产生对于HCV核心诱导的STAT 3活化是必需的。这些结果表明，HCV核心诱导的STAT 3活化在APC改变炎症反应中起着关键作用，导致HCV感染期间抗病毒T细胞反应受损。
Hepatitis C virus (HCV) infection is highly efficient in the establishment of persistent infection, which leads to the development of chronic liver disease and hepatocellular carcinoma. Impaired T cell responses with reduced IFN-gamma production have been reported to be associated with persistent HCV infection. Extracellular HCV core is a viral factor known to cause HCV-induced T cell impairment via its suppressive effect on the activation and induction of pro-inflammatory responses by antigen-presenting cells (APCs). The activation of STAT proteins has been reported to regulate the inflammatory responses and differentiation of APCs. To further characterize the molecular basis for the regulation of APC function by extracellular HCV core, we examined the ability of extracellular HCV core to activate STAT family members(STAT1, -2, -3, -5, and -6). In this study, we report the activation of STAT3 on human monocytes, macrophages, and dendritic cells following treatment with extracellular HCV core as well as treatment with a gC1qR agonistic monoclonal antibody. Importantly, HCV core-induced STAT3 activation is dependent on the activation of the PI3K/Akt pathway. In addition, the production of multifunctional cytokine IL-6 is essential for HCV core-induced STAT3 activation. These results suggest that HCV core-induced STAT3 activation plays a critical role in the alteration of inflammatory responses by APCs, leading to impaired anti-viral T cell responses during HCV infection.