2002 Fiscal Year Final Research Report Summary
Analysis on regulation of macrophage activity by cytokines and endotoxin
| Project/Area Number |
13670140
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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 |
Pathological medical chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
TAKEDA Kiyoshi Research Institute for Microbial Diseases, Research Associate, 微生物病研究所, 助手 (20309446)
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| Project Period (FY) |
2001 – 2002
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| Keywords | macrophage / IL-10 / Stat3 / choronic enterocolitis / knockout mice / cytokine |
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| Research Abstract |
Stat3 plays an essential role in IL-10 signaling pathways. A myeloid cell-specific deletion of Slat3 resulted in inflammatory cytokine production and development of chronic enterocolitis with enhanced Th1 responses in mice. In this study, we analyzed the mechanism by which a Slat3 deficiency in myeloid cells led to the induction of chronic enterocolitis in vivo. Even in the absence of Stat1, which is essential for IFN-γ signaling pathways, Slat3 mutant mice developed chronic enterocolitis. TNF-α/Stat3 double mutant mice developed severe chronic enterocolitis with enhanced Th1 cell development. However, IL-12p40/Stat3 double mutant mice showed normal Th1 responses and no inflammatory change in the colon. RAG2/Stat3 double mutant mice did not develop enterocolitis, either. These findings indicate that overproduction of IL-12p40, which induces potent Th1 responses, is essential for the development of chronic enterocolitis in Stat3 mutant mice. Furthermore, enterocolitis was significantly improved and IFN-γ production by T cells was reduced in ILR4/Stat3 double mutant mice, indicating that TLR4-mediated recognition of microbial components triggers aberrant IL-12p40 production by myeloid cells, leading to the development of enterocolitis. Thus, this study clearly established a sequential innate and acquired immune mechanism for the development of Th1-dependent enterocolitis.
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Research Products
(12 results)
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[Publications] Kobayashi, M., Kweon, M., Kuwata, H., Kiyono, H., Takeda. K., and Akira, S.: "Toll-like receptor-dependent IL12p40 production causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice"In press.
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[Publications] Yamamoto, M., Sato, S., Hemmi, H., Sanjo, H., Uematsu, S., Kaisho, T., Hoshino, K., Takeuchi, O., Kobayashi, M., Fujita, T., Takeda. K., and Akira, S.: "Essential role for T1RAP in activation of the signaling cascade shared by TLR2 and TLR4"Nature. 420. 324-329 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda. K., and Akira, S.: "Small anti-viral compounds activate immune cells via the TLR7-MyD88-dependent signaling pathway"Nature Immunol.. 3. 196-200 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Sato, S., Takeuchi, O., Fujita, T, Tomizawa, H., Takeda. K., Akira, S.: "A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways"Int. Immunol.. 14. 783-791 (2002)
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「研究成果報告書概要(欧文)」より
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