2007 Fiscal Year Final Research Report Summary
Cytokine molecular therapy for intervention of virus infection
| Project/Area Number |
18591131
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
KISHIDA Tsunao Kyoto Prefectural University of Medicine, Graduate School of Medicine, Postdoctor (00370205)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Cvtokine / Virus / MDA5 / Interferon |
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| Research Abstract |
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
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[Journal Article] Interleukin-21 (IL-21) induces Id2 (inhibitor of differentiation 2) and leads to complete abrogation of anaphylaxis in mice2007
Author(s)
Kishida. T. Y. Hiromura, M. Shin-Ya, H. Asada, H. Kuriyama, M. Sugai, A. Shimizu, Y. Yokota, T. Hama, J. Imanishi, Y. Hisa, O. Mazda
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Journal Title
J. Immunol. 179 (12)
Pages: 8554-8561
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Kubo Sonoporation-mediated Transduction of pDNA/siRNA into Joint Synovium in vivo2007
Author(s)
Saito, M., O, Mazda, K, A. Takahashi, Y. Arai, T. Kishida, M. Shin-Ya, A. Inoue, H. Tonomura, K. Sakao, T. Morihara, J. Imanishi, M. Kawata, T. Kubo
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Journal Title
Orthopaed. Res 25 (10)
Pages: 1308-1316
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Soluble TRAIL Gene and Actinomycin D Synergistically Suppressed Multiple Metastasis of TRAIL-resistant Colon Cancer in the Liver2007
Author(s)
Ishii, M., M. Iwai, Y. Harada, T. Kishida, H. Asada, M. Shin-Ya, Y. Itoh, J. Imanishi, T. Okanoue, O. Mazda
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Journal Title
Cancer Letters 245 (1-2)
Pages: 134-143
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Interferon-y Is Causatively Involved in Experimental Inflammatory Bowel Disease in Mice2006
Author(s)
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
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Journal Title
Exp. Clin. Immunol 146(2)
Pages: 330-338
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] IL-21 Triggers both Cellular and Humoral Immune Responses Leading to Therapeutic Antitumor Effects against Head and Neck Squamous Cell Carcinoma2006
Author(s)
Nakano, H., T. Kishida, H. Asada, M. Shin-Ya, T. Shinomiya, J. Imanishi, T. Shimada, S. Nakai, M. Takeuchi, Y. Hisa, O. Mazda
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Journal Title
J. Gene Med 8 (1)
Pages: 90-99
Description
「研究成果報告書概要(欧文)」より
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