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Role of signal transduction pathway in host defense during sepsis

信号转导途径在脓毒症宿主防御中的作用

基本信息

批准号：
17590352
负责人：
MATSUKAWA Akihiro
金额：
$ 2.3万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Cytokine signaling mediated by STAT pathway is negatively regulated by SOCS proteins. In this project, we have investigated the role of SOCS3/5 that inhibit STAT3/4/6 pathway, in innate immunity during sepsis. Mice with a cell-specific overexpression of SOCS5 in T cells (SOCS5Tg) were resistant to the lethality relative to the wild-type (WT) mice. This was due to the enhanced innate immunity in SOCS5Tg mice whereby CD4+T cells with overexpressed SOCS5 augment type-1 immune response of neutrophils and macrophages. Enhanced type-1 response during sepsis was also seen in mice lacking chemokine receptor 8 (CCR8), suggesting an important role of chemokine signaling in innate immunity. In inflammation, resident macrophages, but not other cell types, play a regulatory role through a Stat3 signaling pathway by mediating the anti-inflammatory role of IL-10. Macrophages lacking STAT3 showed decreased expression of Fcy receptor and compliment receptor 1 (CCR1), which was conversely augmented in macrophages lacking SOCS3. This might be responsible for the augmented phagocytic activities of macrophages lacking STAT3/SOCS3. Mice with a cell-specific deletion of STAT3 in phagocytes augmented Thl and Th2 type acquired immune response, possibly due to enhanced APC activities off the cells. On the other hand, mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg mice) were resistant to sepsis due to decreased type-1 response in tissue, resulting in alleviated organ damage. The SOCS3Tg mice were also deleterious in drug-induced hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes.

STAT通路介导的细胞因子信号转导受SOCS蛋白负调控。本课题研究了抑制STAT 3/4/6通路的SOCS 3/5在脓毒症先天免疫中的作用。相对于野生型（WT）小鼠，在T细胞中具有SOCS 5的细胞特异性过表达的小鼠（SOCS 5 Tg）对致死性具有抗性。这是由于SOCS 5 Tg小鼠的先天免疫增强，其中具有过表达SOCS 5的CD 4 +T细胞增强嗜中性粒细胞和巨噬细胞的1型免疫应答。在缺乏趋化因子受体8（CCR 8）的小鼠中也观察到脓毒症期间增强的1型反应，表明趋化因子信号传导在先天免疫中的重要作用。在炎症中，驻留的巨噬细胞，而不是其他细胞类型，通过介导IL-10的抗炎作用，通过Stat 3信号通路发挥调节作用。缺乏STAT 3的巨噬细胞显示Fc γ受体和补体受体1（CCR 1）的表达降低，而在缺乏SOCS 3的巨噬细胞中则相反。这可能是缺乏STAT 3/SOCS 3的巨噬细胞吞噬活性增强的原因。在吞噬细胞中具有STAT 3的细胞特异性缺失的小鼠增强了Thl和Th 2型获得性免疫应答，这可能是由于增强了细胞外的APC活性。另一方面，在T细胞中具有SOCS 3的细胞特异性过表达的小鼠（SOCS 3 Tg小鼠）由于组织中的1型反应降低而对脓毒症具有抗性，从而导致减轻的器官损伤。SOCS 3 Tg小鼠通过增加肝细胞中的STAT 1活化同时减少STAT 3活化，在药物诱导的肝毒性中也是有害的。