Functional analyses on roles of intetferon-IRF-family transcriptional factor

干扰素-IRF家族转录因子的功能分析

• 批准号: 16017220
• 负责人: TAKAOKA Akinori
• 金额: $ 8.64万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16017220/
• 关键词: interferon; IRF family; dendritic cells; apoptosis; Toll-like receptor; p53; innate immunity; antiviral defense; ウイルス感染; 形質細胞様樹状細胞; 炎症性サイトカイン; 転写因子; interferon; IRF family; dendritic cells; apoptosis; Toll-like receptor; p53; innate immunity; antiviral defense; ウイルス感染; 形質細胞様樹状細胞; 炎症性サイトカイン; 転写因子

In this study, we analyzed the molecular mechanism for antiviral defense triggered by interferon-α / (IFN-α/β) and the signalling pathways which lead to type I IFN gene induction by TLR activation. In particular, we focused on IFN-regulatory factors (IRFs), which are known to be essential factors upon viral infection, and have elucidated several novel roles of the IFN-IRF system in activation of innate immune response. First, we found that the level of p53 gene, which is known to encode a tumor suppressor, is upregulated by IFN treatment through activation of ISGF3 transcriptional complex, contributing to enhancement of p53 response to stress signals. We showed that p53 is phosphorylated and activated upon viral infection, and that p53 is essentially involved in the induction of apoptosis in virally infected cells. This result demonstrated an interrelationship between IFN-α/β signaling and p53-mediated response, which provided a novel aspect in terms of a linkage between tumor suppression and immunity. Second, we analyzed various hideficient mice to show that IRF-7 mediates a novel MyD88-dependent pathway for the induction of type I IFN gene expression by TLR9 subfamily members in plasmacytoid dendritic cells (pDCs). In addition, we found a spaciotemporal regulation, by which pDCs are capable to produce high levels of IFN- α/β. On the other hand, IRF-5 is found to be essentially involved in TLR-mediated production of proinflammatory cytokines. Recently, we also found that IRF-5 is activated upon viral infection and plays a role in virus-induced apoptosis in a distinct manner from p53. Another IRF-family member, IRF-4, is shown to be a negative regulator of IRF-5 by competitively inhibiting the interaction of IRF-5 with MyD88. Thus, we demonstrated that IRF-family transcriptional factors are critical downstream mediators of TLRs to regulate the activation of innate immune response.

在这项研究中，我们分析了干扰素-α /（IFN-α /β）触发的抗病毒防御的分子机制，以及导致TLR激活导致I型IFN基因诱导的信号传导途径。特别是，我们专注于IFN调节因子（IRF），这些因素是病毒感染的基本因素，并阐明了IFN-IRF系统在激活先天免疫反应激活的几个新作用。首先，我们发现p53基因的水平（已知可以编码肿瘤抑制剂）通过激活ISGF3转录复合物进行更新，从而更新，这有助于增强对应力信号的p53响应。我们表明p53在病毒感染后被磷酸化并激活，并且p53基本上参与了病毒感染细胞的凋亡。该结果表明，IFN-α/β信号传导与p53介导的反应之间存在相互关系，这在肿瘤抑制与免疫力之间的联系方面提供了新的方面。其次，我们分析了各种藏匿的小鼠，以表明IRF-7介导了一种新型的MyD88依赖性途径，以通过TLR9亚家族成员在静脉瘤树突状细胞（PDC）中诱导I型IFN基因表达。此外，我们发现了一个时空调节，PDC能够产生高水平的IFN-α/β。另一方面，发现IRF-5基本上与TLR介导的促炎细胞因子的产生有关。最近，我们还发现，IRF-5在病毒感染中被激活，并以与p53不同的方式在病毒诱导的凋亡中起作用。通过竞争性抑制IRF-5与MYD88的相互作用，另一个IRF家庭成员IRF-4被证明是IRF-5的负调节剂。这就是我们证明IRF家庭转录因子是TLR的关键下游介质，以调节先天免疫反应的激活。