Hepatitis C Virus and Disrupted Interferon Signaling Promote Lymphoproliferation via Type II CD95 and Interleukins
Hepatitis C Virus and Disrupted Interferon Signaling Promote Lymphoproliferation via Type II CD95 and Interleukins
复制标题
DOI：
10.1053/j.gastro.2009.03.061
复制
发表时间：
2009-07-01
期刊：
影响因子：
29.4
通讯作者：
Kohara, Michinori
中科院分区：
文献类型：
--
作者：
Machida, Keigo;Tsukiyama-Kohara, Kyoko;Kohara, Michinori
背景与目的：与干扰素信号转导中断和慢性丙型肝炎病毒感染相关的淋巴细胞增殖的分子机制尚不清楚。淋巴瘤是丙型肝炎病毒感染的肝外表现；我们试图阐明这些过程的分子机制。方法：建立可诱导持续表达丙型肝炎病毒结构蛋白的干扰素调节因子-1缺失(IRF-1(-/-))小鼠(IRF-1/CN2小鼠)。所有小鼠(n=900)在Cre/loxP转换后至少观察600天。进行了组织学分析，以及淋巴增殖、对Fas诱导的细胞凋亡的敏感性、结肠)、形成和细胞因子产生的分析。与这些过程相关的蛋白质也被评估。结果：IRF-1/CN2小鼠具有极高的淋巴瘤和淋巴增殖性疾病的发生率，并表现出增加的死亡率。IRF-1的阻断降低了对Fas诱导的细胞凋亡的敏感性，并降低了caspase-3/7和caspase-9信使RNA种类和酶活性。此外，IRF-1/CN2小鼠表现出caspase-3/7和caspase-9活性降低，IL-2、IL-10和Bcl2水平升高，Bcl2表达增加，从而促进淋巴细胞的致癌转化。脾细胞中的IL-2和IL-10由丙型肝炎病毒核心蛋白诱导。结论：干扰素信号的缺失导致了淋巴瘤的发生，提示淋巴细胞与肝脏存在不同的信号传导。在这种小鼠模型中，丙型肝炎病毒的表达和干扰素信号的破坏协同作用促进了淋巴增殖，这将是开发针对淋巴增殖途径的治疗药物的重要工具。
BACKGROUND & AIMS: The molecular mechanisms of lymphoproliferation associated with the disruption of interferon (IFN) signaling and chronic hepatitis C virus (HCV) infection are poorly understood. Lymphomas are extrahepatic manifestations of HCV infection; we sought to clarify the molecular mechanisms of these processes. METHODS: We established interferon regulatory factor-1-null (irf-1(-/-)) mice with inducible and persistent expression of HCV structural proteins (irf-1/CN2 mice). All the mice (n = 900) were observed for at least 600 days after Cre/loxP switching. Histologic analyses, as well as analyses of lymphoproliferation, sensitivity to Fas-induced apoptosis, colon), formation, and cytokine production, were performed. Proteins associated with these processes were also assessed. RESULTS: Irf-1/CN2 mice had extremely high incidences of lymphomas and lymphoproliferative disorders and displayed increased mortality. Disruption of irf-1 reduced the sensitivity to Fas-induced apoptosis and decreased the levels of caspases-3/7 and caspase-9 messenger RNA species and enzymatic activities. Furthermore, the irf-1/CN2 mice showed decreased activation of caspases-3/7 and caspase-9 and increased levels of interleukin (IL)-2, IL-10, and Bcl-2, as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes. IL-2 and IL-10 were induced by the HCV core protein in splenocytes. CONCLUSIONS: Disruption of IFN signaling resulted in development of lymphoma, indicating that differential signaling occurs in lymphocytes compared with liver. This mouse model, in which HCV expression and disruption of IFN signaling synergize to promote lymphoproliferation, will be an important tool for the development of therapeutic agents that target the lymphoproliferative pathway.