| Project/Area Number |
13307013
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | Osaka University |
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Principal Investigator |
SHIZUO Akira Osaka University, Research Institute for Microbial Diseases, Professor, 微生物病研究所, 教授 (50192919)
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| Co-Investigator(Kenkyū-buntansha) |
HOSHINO Katsuaki Osaka University, Research Institute for Microbial Diseases, Research Associate, 微生物病研究所, 助手 (50324843)
TAKEDA Kiyoshi Osaka University, Research Institute for Microbial Diseases, Research Associate, 微生物病研究所, 助手 (20309446)
KAISHO Tsuneyasu Osaka University, Research Institute for Microbial Diseases, Assistant Professor, 微生物病研究所, 助教授 (60224325)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥55,900,000 (Direct Cost: ¥43,000,000、Indirect Cost: ¥12,900,000)
Fiscal Year 2002: ¥21,580,000 (Direct Cost: ¥16,600,000、Indirect Cost: ¥4,980,000)
Fiscal Year 2001: ¥34,320,000 (Direct Cost: ¥26,400,000、Indirect Cost: ¥7,920,000)
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| Keywords | Innate immunity / TLR / signal transduction / knockout mice / MyD88 / infection |
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| Research Abstract |
Signal transduction via Toll-like receptors (TLRs) originates from the Toll/interleukin-1 receptor (TIR) domain, to which a TIR domain-bearing common adapter, MyD88 binds. Although cytokine production is completely abolished in MyD88-deficient mice, some LPS responses including induction of IFN-inducible genes and maturation of dendritic cells are still observed. Recently, another adapter named TIRAP/Mal has been cloned as a molecule that specifically associates with TLR4 and may explain the MyD88-independent response. To assess the physiological role of TIRAP/Mal, we generated mice lacking TIRAP. LPS-induced splenocyte proliferation and cytokine production were abolished in TIRAP-deficient mice. Similar to MyD88-deficient mice, LPS activation of NF-kB and MAP kinases was induced with delayed kinetics. Expression of IFN-inducible genes as well as maturation of dendritic cells was observed. They also displayed defective response to TLR2 ligands, but not to other stimuli that activate TLR3, TLR7 or TLR9. These results demonstrate that TIRAP is not specific to the TLR4 signaling or does not participate in the MyD88-independent pathway, but rather TIRAP plays a crucial role in the MyD88-dependent signaling pathway shared by TLR2 and TLR4. These results further indicate that TIR domain-containing adaptors provide specificity of TLR signaling. Therefore, we searched TIR domain-containing molecules in database, and we identified a novel TIR domain containing molecule, named TRIF (TIR domain containing adaptor inducing interferon-b). TRIF activated NF-kB like MyD88 and TIRAP. In addition, unlike MyD88 and TIRAP, TRIF activated the lFN-b promoter. Dominant negative TRIF, but not MyD88 and TIRAP, inhibited TLR3-dependent activation of NF-kB and the IFN-b promoter. TRIF associated with TLR3 and IRF-3, which acts in the MyD88-independent signaling. These findings suggest that TRIF plays an important role in the TLR signaling, particularly in the MyD88-independent pathway.
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