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Association of between HCV induced mitochondria dysfunction and viral response by interferon in hepatic iron overloaded

HCV诱导的线粒体功能障碍与肝铁超载中干扰素的病毒反应之间的关联

基本信息

批准号：
22590750
负责人：
KORENAGA Masaaki
金额：
$ 2.91万
依托单位：
Research Institute, International Medical Center of Japan (2011-2012)Kawasaki Medical School (2010)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590750/
关键词：
ミトコンドリア鉄過剰状態肝発癌酸化ストレス MAVS IFN C型慢性肝炎 Hepcidin PolyIC

项目摘要

We previously reported that HCC developed through the oxidative stress in iron-overloaded transgenic mice expressing the hepatitis C virus (HCV) polyprotein (HCV TgM) (Gastroenterology;130: 2006) Oxidative stress is one of the pathophysiologic mechanisms involved in HCV-associated liver injury and hepatocarcinogenesis. The aim of this study was to clarify whether iron-induced oxidative stress affects HCV replication in full genomic HCV replicon cells. Methods: Various concentration of Fe(II)SO4, Fe(III)(NO3)3, FeCl2, FeCl3, Holo-transferrin apo-transferring or IFNα was added to the genome length HCV-RNA replicon (OR6) cells. Using reporter assay system, HCV replication was assessed. We also measured cellular reactive oxygen sepsis (ROS) production by DCF assay and the expression levels of HCV core protein by western blot. Result：Ferrous and ferric ions significantly inhibited HCV replication and the levels of core protein at the concentration of iron less than 1uM. However, only ferrous ions increased ROS production, suggesting that ferric ions may have inhibited HCV replication through its cytotoxicity Additional IFN treatment showed additive inhibition of HCV replication. Conclusion: Although iron- induced oxidative stress accelerates hepatocarcinogenesis, it may work as an anti-HCV factor in patients with chronic hepatitis C. These data suggested that we should avoid touse antioxidant agents during IFN therapy.

我们先前报道了在表达丙型肝炎病毒（HCV）多聚蛋白（HCV TgM）的铁超载转基因小鼠中通过氧化应激发展HCC（Gastroenterology;130：2006）。氧化应激是HCV相关肝损伤和肝癌发生的病理生理机制之一。本研究的目的是澄清铁诱导的氧化应激是否影响HCV复制在全基因组HCV复制子细胞。研究方法：将不同浓度的Fe（II）SO_4、Fe（III）（NO_3）_3、FeCl_2、FeCl_3、全转铁蛋白脱辅基转移或IFNα加入基因组长度的HCV-RNA复制子（OR_6）细胞中。用报告基因检测系统检测HCV复制情况。我们还通过DCF法检测细胞活性氧（ROS）的产生，并通过Western印迹法检测HCV核心蛋白的表达水平。结果：在铁离子浓度小于1 μ M时，亚铁离子和三价铁离子均能显著抑制HCV的复制和核心蛋白的表达。然而，只有亚铁离子增加ROS的产生，这表明铁离子可能通过其细胞毒性抑制HCV复制。结论：虽然铁诱导的氧化应激加速了肝癌的发生，但它可能在慢性丙型肝炎患者中作为抗HCV因子发挥作用。提示IFN治疗中应避免使用抗氧化剂。