Hepatitis B virus X protein stimulates IL-6 expression in hepatocytes via a MyD88-dependent pathway
Hepatitis B virus X protein stimulates IL-6 expression in hepatocytes via a MyD88-dependent pathway
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乙型肝炎病毒 X 蛋白通过 MyD88 依赖性途径刺激肝细胞中 IL-6 的表达
DOI：
10.1016/j.jhep.2010.08.006
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发表时间：
2011-01-01
影响因子：
25.7
通讯作者：
Liu, Wei
中科院分区：
文献类型：
--
作者：
Xiang, Wen-Qing;Feng, Wen-Feng;Liu, Wei
背景和目标：B型肝炎病毒（HBV）X蛋白（HBx）通过激活信号转导通路和影响肝细胞基因转录而参与HBV相关的致癌作用。我们的目的是探讨HBx诱导的白细胞介素-6（IL-6），刺激肝细胞癌development.Methods的主要炎症介质之一的生产的潜在机制：HBx过表达的肝细胞和肝癌细胞系和IL-6的表达水平进行了测定，通过定量RT-PCR和ELISA。使用特异性抗磷蛋白抗体通过Western印迹法测定IRAK-1、ERK/p38和NF-κ B的活化。结果：HBx在肝细胞和肝癌细胞中的表达可显著增强IL-6的合成和分泌。这些细胞中MyD 88的功能障碍阻止了HBx触发的IL-6产生。HBx表达还激活MyD 88的下游信号蛋白，包括IRAK-1、ERK/p38和NF-κ B。这些信号分子的失活也阻断了IL-6的合成。结论：在肝细胞和肝癌细胞中，HBx以MyD 88依赖的方式刺激IL-6的产生，提示肝实质细胞是HBV感染肝脏微环境中高水平IL-6的额外来源。HBx可能通过这种作用机制参与HBV介导的肝癌发生。(C)2010年由Elsevier B. V.代表欧洲肝脏研究协会发表。
Background & Aims: Hepatitis B virus (HBV) X protein (HBx) has been implicated in HBV-associated carcinogenesis by activating signal transduction pathways and influencing gene transcription in liver cells. We aimed to investigate the underlying mechanisms for HBx-induced production of interleukin-6 (IL-6), one of the major inflammatory mediators that stimulate hepatocellular carcinoma development.Methods: HBx was overexpressed in hepatic and hepatoma cell lines and IL-6 expression levels were measured by quantitative RT-PCR and ELISA. The activation of IRAK-1, ERKs/p38, and NF-kappa B was determined by Western blotting using specific anti-phosphoprotein antibodies. The role of MyD88 in these processes was analyzed by MyD88 RNAi and expression of an inactive MyD88 mutant.Results: Expression of HBx in hepatic and hepatoma cells led to a dramatic enhancement of IL-6 synthesis and secretion. Dysfunction of MyD88 in these cells prevented the HBx-triggered IL-6 production. HBx expression also activated downstream signaling proteins of MyD88 including IRAK-1, ERKs/p38, and NF-kappa B. Inactivation of these signaling molecules blocked IL-6 synthesis as well. HBx-stimulated the expression of MyD88.Conclusions: In hepatocytes and hepatoma cells, HBx stimulates the production of IL-6 in a MyD88-dependent manner, indicating that parenchymal liver cells are an additional source of high levels of IL-6 in the HBV-infected liver microenvironment. HBx could be involved in HBV-mediated liver carcinogenesis, through this mechanism of action. (C) 2010 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.