2004 Fiscal Year Final Research Report Summary
Recognition of dsRNA by Toll-like receplor 3
| Project/Area Number |
15590447
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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 |
Immunology
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| Research Institution | Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases |
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Principal Investigator |
MATSUMOTO Misako Osaka Medical Center for Cancer, Dept.of Immunology, Researcher, 研究所, 部門長 (30332456)
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| Co-Investigator(Kenkyū-buntansha) |
SEYA Tsukasa Hokkaido University, Graduate School of Medicine, Dept.of Microbiology and Immunology, Professor, 大学院・医学研究科・病態制御医学講座, 教授 (10301805)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Innate immunity / Toll-like receptor / Adaptor molecule / Dendritic cell / Type 1 interferon / double-stranded RNA / Viral infection / Interferon regulatory factor |
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| Research Abstract |
Toll-like receptor 3(TLR3) recognizes dsRNA and transmits signals to activate NF-κB and the IFN-β promoter independent of the adaptor molecules MyD88 and Mal/TIRAP. We have identified an alternative adaptor, designated Toll-interleukin 1 receptor domain(TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-β promoter in response to poly(I:C), a syntetic analog of dsRNA. TICAM-1, when overexpressed, activated NF-κB and interferon regulatory factor(IRF)-3, a critically important transcription factor for IFN-β gene expression. RNA interference-mediated knockdown of TLR3 or TICAM-1, but not of MyD88 or Mal/TIRAP, significantly reduced IFN-β production induced by poly(I:C) in human fibloblasts and HeLa cells. Thus, dsRNA-TLR3-dependent production of IFN-β is mediated mainly by TICAM-1. Furthermore, we cloned an additional adaptor molecule, TICAM-2, that physically bridges TLR4 and TICAM-1 and functionally transmits LPS-TLR4 signaling to TICAM-1, which in turn activates IRF-3 leading to produce IFN-β. This TICAM-1-dependent pathway forms part of the MyD88-independent cellular immune response. Immunofluorescence staining and con focal microscopic analysis using anti-human TLR3 mAb (TLR3.7) revealed that TLR3 localized to specific unidentified intracellular vesicles in both monocyte-derived immature DCs and CD11c^+ blood DCs. TLR3-mediated signaling required endosomal maturation. These results suggest that the TLR3-TICAM-1 pathway plays an important role in sensing the extracellular dsRNA, which participates in an antiviral immune response.
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Research Products
(46 results)
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[Journal Article] The regulator of complement activation (RCA) locus in the chicken : Identification of the chicken RCA gene cluster and functional characterization of the RCA proteins.2005
Author(s)
Oshiumi, H., K.Shida, Y.Kimura, J.Katoh, S.Ohba, Y.Tamaki, T.Hattori, N.Yamada, N.Inoue, M.Matsumoto, S.Mizuno, T.Seya.
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Journal Title
Description
「研究成果報告書概要(和文)」より
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[Journal Article] A short consensus repeat-containing complement regulatory protein of Lamprey that participates in cleavage of lamprey complement 3.2004
Author(s)
Kimura, Y., N.Inoue, A.Fukui, H.Oshiumi, M.Matsumoto, M.Nonaka, S.Kuratani, T.Fujita, M.Nonaka, T.Seya.
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Journal Title
J.Immunol. 173
Pages: 1118-1128
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection.2003
Author(s)
Honda, K., S.Sakaguchi, C.Nakajima, A.Watanabe, H.Yanai, M.Matsumoto, T.Ohteki, T.Kaisho, A.Takaoka, S.Akira, T.Seya, T.Taniguchi.
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Journal Title
Proc.Natl.Acad.Sci.U.S.A. 100
Pages: 10872-10877
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection.2003
Author(s)
Honda, K., S.Sakaguchi, C.Nakajima, A.Watanabe, H.Yanai, M.Matsumoto, T.Ohteki, T.Kaisho, A.Takaoka, S.Akira, T.Seya, T.Taniguchi
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Journal Title
Proc.Natl.Acad.Sci.U.S.A. 100
Pages: 10872-10877
Description
「研究成果報告書概要(欧文)」より
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