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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

基本信息

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

项目摘要

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.

本研究分析了干扰素-α /（IFN-α/β）引发抗病毒防御的分子机制以及TLR激活诱导I型IFN基因的信号通路。特别是，我们专注于IFN-调节因子（IRF），这是已知的病毒感染后的重要因素，并阐明了几个新的IFN-IRF系统在激活先天免疫反应的作用。首先，我们发现已知编码肿瘤抑制因子的p53基因的水平被IFN处理通过激活ISGF 3转录复合物而上调，有助于增强p53对应激信号的反应。我们发现p53在病毒感染后被磷酸化和激活，并且p53基本上参与了病毒感染细胞的凋亡诱导。这一结果证明了IFN-α/β信号传导和p53介导的应答之间的相互关系，这为肿瘤抑制和免疫之间的联系提供了一个新的方面。第二，我们分析了各种hi缺陷小鼠，以表明IRF-7介导了一种新的MyD 88依赖性途径，用于诱导浆细胞样树突状细胞（pDC）中TLR 9亚家族成员的I型IFN基因表达。此外，我们还发现了pDC产生高水平IFN- α/β的时空调控机制。另一方面，发现IRF-5基本上参与TLR介导的促炎细胞因子的产生。最近，我们还发现IRF-5在病毒感染后被激活，并以与p53不同的方式在病毒诱导的细胞凋亡中发挥作用。另一个IRF家族成员IRF-4通过竞争性抑制IRF-5与MyD 88的相互作用而被证明是IRF-5的负调节剂。因此，我们证明了IRF家族转录因子是调节先天免疫应答激活的TLR的关键下游介质。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction

DOI：
10.1038/nature03547
发表时间：
2005-04-21
期刊：
NATURE
影响因子：
64.8
作者：
Honda, K;Ohba, Y;Taniguchi, T
通讯作者：
Taniguchi, T

Integration of IFN-α/β sinalling to p53 responses in tumour suppression and anitiviral defense.

IFN-α/β 信号与 p53 反应在肿瘤抑制和抗病毒防御中的整合。

DOI：
发表时间：
2003
期刊：
Nature 424
影响因子：
0
作者：
Takaoka;A.;Hayakawa;S.;Yanai;H.;Stoiber;D.;Negishi H.;Kikuchi;H.;Sasaki;S.;Imai;K.;Shibue;T.;Honda;K.;Taniguchi;T.
通讯作者：
T.

Type I interferon system and IRF family of transcription factors in host defense regulation.

I 型干扰素系统和 IRF 转录因子家族在宿主防御调节中的作用。

DOI：
发表时间：
2005
期刊：
Proc. Jpn. Acad. Vol.81
影响因子：
0
作者：
Taniguchi T;Takaoka A.
通讯作者：
Takaoka A.

Negative regulation of Toll-like receptor signaling by IRF-4.Proc.Natl.Acad.Sci.USA.

IRF-4.Proc.Natl.Acad.Sci.USA 对 Toll 样受体信号传导的负调控。

DOI：
发表时间：
2005
期刊：
Proc.Natl.Acad.Sci.USA. Vol.102
影响因子：
0
作者：
Negishi;H.;Ohba;Y.;Yanai;H.;Takaoka;A.;Honma;K.;Yui;K.;Matsuyama;T.;Taniguchi;T.;Honda;K.
通讯作者：
K.

IRF-7 is the master regulator of type-I interferon-dependent immune responses