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Cytokine molecular therapy for intervention of virus infection

干预病毒感染的细胞因子分子治疗

基本信息

批准号：
18591131
负责人：
KISHIDA Tsunao
金额：
$ 2.47万
依托单位：
Kyoto Prefectural University of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591131/
关键词：
Cvtokine Virus MDA5 Interferon 感染症微生物

项目摘要

Interleukin-27 (IL-27) is a heterodimeric cytokine composed of two polypeptide subunits, IL-27 p28 and EBV-induced protein 3 (Ebi3). The IL-27 signal is mediated through the heterodimeric receptor complex that consists of IL-27R_(WSX-1, TCCR)and gp130 and is expressed on various cells including naive CD4 positive T cells. Activation of JAK1/STAT1 pathway is crucially involved in the signal transduction downstream of the IL-27R complex. IL-27 provokes naive CD4 positive T cells to express T-bet and, subsequently, IL-12R62. IL-27 sequentially cooperates with IL-12 to induce initiation and maintenance of Th1 immune responses. IL-27 also synergize with IL-12 to induce interferon (IFN)-y production. Recently it was shown that generation of Th17 cells is suppressed by IL-27 in a STAT1 dependent manner. Taken together, IL-27 is involved in the key step for Th1 commitment where naive Th precursor cells commence differentiation into Th1 cells, and it is now considered that IL-27 is associated w … More ith many human diseases including malignant, allergic and inflammatory disorders. In this project, we found that IL-27 is also involved in a novel defense mechanism against virus infection. C57BI/6 mice that had been infected with Encephalomyocarditis virus (EMCV) were transfected in vivo with IL-27 gene, and their longevity was analyzed. All the control mice that received the virus but not IL-27 gene died within 10 days after the infection, whereas survival rate of the IL-27 gene-transfected mice remained 100% during this period. To clarify the mechanism of the anti-virus activity of IL-27, we also performed in vitro experiments, which strongly suggested that IL-27 directly acted on virus-infected cardiomyocytes to suppress virus replication, whereas induction of acquired immune responses did not contribute to the virus clearance. As an intracellular innate machinery against virus infection, MDA5-mediated pathway is widely known, but little is known on molecular mechanisms to regulate MDA5 expression. Then we assessed whether MDA5 participates in the IL-27-mediated virus suppression. Primary cardiac muscle cells were established form the day 16 mouse embryos and stimulated with IL-27, which led to drastic induction of mRNA for MDA5. Infected with EMCV, the IL-27-treated cells showed massive production of IFN-6 immediately after the infection, which was in sharp contrast to the lower level of IFN production by the cells that were not treated with IL-27. Specific silencing of MDA5 by means of the short interfering RNA completely cancelled the and-virus effect that was otherwise produced in cardiomyocytes after the IL-27 provocation. These findings indicate that IL-27 signaling augments expression of MDA5 in cardiac muscle cells, resulting in a strengthening of MDA5 pathway triggered by virus infection, which in turn generates robust induction of type I IFN at an early phase of infection to effectively suppress virus replication. Less

白细胞介素-27（IL-27）是由IL-27 p28和EBV诱导蛋白3（Ebi 3）两个多肽亚基组成的异源二聚体细胞因子。IL-27信号通过由IL-27 R_（WSX-1，TCCR）和gp 130组成的异源二聚体受体复合物介导，并在包括初始CD 4阳性T细胞在内的多种细胞上表达。JAK 1/STAT 1通路的激活在IL-27 R复合物下游的信号转导中至关重要。IL-27激发初始CD 4阳性T细胞表达T-bet，随后表达IL-12 R62。IL-27依次与IL-12协同诱导Th 1免疫应答的启动和维持。IL-27还与IL-12协同诱导干扰素（IFN）-γ产生。最近显示，IL-27以STAT 1依赖性方式抑制Th 17细胞的产生。综上所述，IL-27参与了Th 1定型的关键步骤，其中初始Th前体细胞开始分化为Th 1细胞，现在认为IL-27与Th 1细胞的分化有关。 ...更多信息与包括恶性、过敏性和炎性病症在内的许多人类疾病相关。在这个项目中，我们发现IL-27也参与了一种新的抗病毒感染的防御机制。用IL-27基因转染脑心肌炎病毒（Encephalomyocarditis virus，EMCV）感染的C57 BI/6小鼠，观察其寿命。所有接受病毒但未接受IL-27基因的对照小鼠在感染后10天内死亡，而IL-27基因转染小鼠的存活率在此期间保持100%。为了阐明IL-27抗病毒活性的机制，我们还进行了体外实验，这强烈地表明IL-27直接作用于病毒感染的心肌细胞以抑制病毒复制，而诱导获得性免疫应答并不有助于病毒清除。MDA 5介导的途径作为抗病毒感染的细胞内先天机制已广为人知，但对调节MDA 5表达的分子机制知之甚少。然后我们评估了MDA 5是否参与IL-27介导的病毒抑制。从第16天的小鼠胚胎建立原代心肌细胞，并用IL-27刺激，这导致MDA 5的mRNA的急剧诱导。用EMCV感染，IL-27处理的细胞在感染后立即显示出大量的IFN-6产生，这与未用IL-27处理的细胞的较低水平的IFN产生形成鲜明对比。特异性沉默的MDA 5的短干扰RNA的装置完全取消了和病毒的影响，否则产生的心肌细胞后，IL-27的挑衅。这些发现表明，IL-27信号转导增强心肌细胞中MDA 5的表达，导致由病毒感染触发的MDA 5途径的加强，这反过来在感染的早期阶段产生I型IFN的强诱导，以有效抑制病毒复制。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

lnterleukin-21(lL-21)administration into the nostril alleviates murine allergic rhinitis

将白细胞介素 21 (lL-21) 注入鼻孔可缓解小鼠过敏性鼻炎

DOI：
发表时间：
2007
期刊：
J.Immunol 179(10)
影响因子：
0
作者：
Hiromura;Y.;et. al.
通讯作者：
et. al.

Interleukin-21 (IL-21) administration into the nostril alleviates murine allergic rhinitis

将白细胞介素 21 (IL-21) 注入鼻孔可缓解小鼠过敏性鼻炎

DOI：
发表时间：
2007
期刊：
J. Immunol 179 (10)
影响因子：
0
作者：
Hiromura;Y.;T. Kishida;H. Nakano;T. Hama;J. Imanishi;Y. Hisa;O. Mazda
通讯作者：
O. Mazda

Interferon-y Is Causatively Involved in Experimental Inflammatory Bowel Disease in Mice

干扰素-y 与小鼠实验性炎症性肠病有关

DOI：
发表时间：
2006
期刊：
Exp. Clin. Immunol 146(2)
影响因子：
0
作者：
Ito;R.;M. Shin-Ya;T. Kishida;A. Urano;R. Takada;J. Sakagami;J. Imanishi;M. Kita;Y. Ueda;Y. Iwakura;Keisho;Kataoka;T. Okanoue;O. Mazda
通讯作者：
O. Mazda

IL-21 Triggers both Cellular and Humoral Immune Responses Leading to Therapeutic Antitumor Effects against Head and Neck Squamous Cell Carcinoma.

IL-21 触发细胞和体液免疫反应，从而产生针对头颈鳞状细胞癌的治疗性抗肿瘤作用。

DOI：
发表时间：
2006
期刊：
J.Gene Med. 8(1)
影响因子：
0
作者：
Nakano;H.;T.Kishida;H.asada;M.Shin-Ya;T.Shinomiya;J.Imanishi;T.Shimada;S.Nakai;M.Takeuchi;Y.Hisa;*O.Mazda
通讯作者：
*O.Mazda

Therapeutic RNA Interference of malignant malanoma by electrotransfer of small interfering RNA targeting Mitf.

通过电转移靶向 Mitf 的小干扰 RNA 来治疗性 RNA 干扰恶性恶性瘤。