Analysis on regulation of macrophage activity by cytokines and endotoxin

细胞因子和内毒素对巨噬细胞活性的调节分析

• 批准号: 13670140
• 负责人: TAKEDA Kiyoshi
• 金额: $ 2.3万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670140/
• 关键词: macrophage; IL-10; Stat3; choronic enterocolitis; knockout mice; cytokine; STAT3

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.

Stat3在IL-10信号通路中起重要作用。髓细胞特异性缺失Slat3导致炎症细胞因子的产生和慢性小肠结肠炎的发展，Th1反应增强。在这项研究中，我们分析了髓细胞中Slat3缺乏导致体内慢性小肠结肠炎的机制。即使缺乏IFN-γ信号通路所必需的Stat1， Slat3突变小鼠也会发生慢性小肠结肠炎。TNF-α/Stat3双突变小鼠发生严重慢性小肠结肠炎，Th1细胞发育增强。然而，IL-12p40/Stat3双突变小鼠显示正常的Th1反应，结肠无炎症变化。RAG2/Stat3双突变小鼠也未发生小肠结肠炎。这些发现表明，过量产生IL-12p40，诱导强效Th1反应，是Stat3突变小鼠慢性小肠结肠炎发展的必要条件。此外，在ILR4/Stat3双突变小鼠中，小肠结肠炎明显改善，T细胞产生IFN-γ减少，表明tlr4介导的微生物成分识别触发髓细胞异常产生IL-12p40，导致小肠结肠炎的发生。因此，本研究明确了th1依赖性小肠结肠炎发生的先天和获得性序贯免疫机制。

项目成果

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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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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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Takeda, K., Akira, S.et al.: "Toll-like receptors"Annu. ReV. Immunol.. 21. 335-376 (2003)

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Takeda, K., and Akira, S.: "Roles of Toll-like receptors in innate immune responses"Genes to Cells. 6. 733-742 (2001)

Takeda, K. 和 Akira, S.：“Toll 样受体在先天免疫反应中的作用”基因与细胞。