Hepatitis C Virus Infection Induces Inflammatory Cytokines and Chemokines Mediated by the Cross Talk between Hepatocytes and Stellate Cells
Hepatitis C Virus Infection Induces Inflammatory Cytokines and Chemokines Mediated by the Cross Talk between Hepatocytes and Stellate Cells
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DOI：
10.1128/jvi.00974-13
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发表时间：
2013-07-01
影响因子：
5.4
通讯作者：
Shimotohno, Kunitada
中科院分区：
文献类型：
--
作者：
Nishitsuji, Hironori;Funami, Kenji;Shimotohno, Kunitada
炎症细胞因子和趋化因子在病毒感染期间的炎症中发挥重要作用。丙型肝炎病毒（HCV）是一种亲肝RNA病毒，与慢性肝脏炎症、纤维化和肝细胞癌密切相关。在 HCV 相关疾病的进展过程中，肝星状细胞 (HSC) 有助于 HCV 感染引发的炎症反应。然而，HCV 感染期间介导 HSC 诱导的慢性炎症的潜在分子机制尚不完全清楚。通过在体外将 HSC 与 HCV 感染的肝细胞共培养，我们发现 HSC 刺激 HCV 感染的肝细胞，导致促炎细胞因子和趋化因子的表达，例如白细胞介素 6 (IL-6)、IL-8、巨噬细胞炎症蛋白 1 α (MIP-1 α) 和 MIP-1 β。此外，我们发现这种效应是由 HSC 分泌的 IL-1 α 介导的。 HCV 感染增强了 CCAAT/增强子结合蛋白 (C/EBP) β mRNA 的产生，而 HSC 依赖性 IL-1 α 的产生有助于刺激 HCV 感染的肝细胞中 C/EBP β 靶细胞因子和趋化因子。与此结果一致，在添加 HSC 条件培养基后，HCV 感染的肝细胞中 C/EBP β mRNA 的敲低导致细胞因子和趋化因子的产生减少。 HSC 条件培养基诱导肝细胞中的细胞因子和趋化因子需要在生产性 HCV 感染期间尚未确定的进入后事件。 HSC 和 HCV 感染的肝细胞之间的交互作用是炎症介导的 HCV 相关疾病的一个关键特征。
Inflammatory cytokines and chemokines play important roles in inflammation during viral infection. Hepatitis C virus (HCV) is a hepatotropic RNA virus that is closely associated with chronic liver inflammation, fibrosis, and hepatocellular carcinoma. During the progression of HCV-related diseases, hepatic stellate cells (HSCs) contribute to the inflammatory response triggered by HCV infection. However, the underlying molecular mechanisms that mediate HSC-induced chronic inflammation during HCV infection are not fully understood. By coculturing HSCs with HCV-infected hepatocytes in vitro, we found that HSCs stimulated HCV-infected hepatocytes, leading to the expression of proinflammatory cytokines and chemokines such as interleukin-6 (IL-6), IL-8, macrophage inflammatory protein 1 alpha (MIP-1 alpha), and MIP-1 beta. Moreover, we found that this effect was mediated by IL-1 alpha, which was secreted by HSCs. HCV infection enhanced production of CCAAT/enhancer binding protein (C/EBP) beta mRNA, and HSC-dependent IL-1 alpha production contributed to the stimulation of C/EBP beta target cytokines and chemokines in HCV-infected hepatocytes. Consistent with this result, knockdown of mRNA for C/EBP beta in HCV-infected hepatocytes resulted in decreased production of cytokines and chemokines after the addition of HSC conditioned medium. Induction of cytokines and chemokines in hepatocytes by the HSC conditioned medium required a yet to be identified postentry event during productive HCV infection. The cross talk between HSCs and HCV-infected hepatocytes is a key feature of inflammation-mediated, HCV-related diseases.