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Analysis of signal transduction pathway in innate immunity during sepsis

脓毒症先天免疫信号转导通路分析

基本信息

批准号：
15590349
负责人：
MATSUKAWA Akihiro
金额：
$ 2.3万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590349/
关键词：
sepsis innate immunity signal transduction cytokine chemokine neeutrophil macrophage 自然免疫全身性炎症症候群

项目摘要

Stat3 is a transcription factor mediating anti-inflammatory properties of IL-10. To understand the role of Stat3 in inflammation, mice with targeted disruption of Stat3 in macrophages and neutrophils were succumbed to septic peritonitis. The mice displayed an excessive local and systemic inflammation relative to the control mice, an event that was accompanied by substantial increases in the level of multiple cytokines. Hepatic and renal injury was significantly exacerbated in mice with Stat3 deficiency. In addition, the mice exhibited an increased lethality after intraperitoneal inoculation of live bacteria recovered. In vitro, productions of inflammatory cytokines were significantly augmented when cells were stimulated with a synthetic lipopeptide, macrophage-activating lipopeptide-2(MALP-2) and LPS. Thus, macrophage/neutrophil-specific Stat3 is crucial in modulating multiple organ failure associated with systemic inflammation. Experiments were further carried out to understand the pr … More ecise role of Stat3 in inflammation. For this purpose, mice lacking Stat3 in macrophages and neutrophils were intraperitoneally injected with thioglycollate and the subsequent inflammatory responses were investigated. We obtained evidence that Stat3 expressed in resident macrophages, but not other cell types, play a central role in the regulation of inflammatory response. Resident macrophages are important in triggering inflammation, but the cells in the same breath appear to control inflammation through Stat3 signaling pathway.C57BL/6 and BALB/c mice are prototypical Th1- and Th2-type mouse strains, respectively. We attempted to characterize the innate immune response of macrophages from these mouse strains. We demonstrated that macrophages from BALB/c mice showed impaired bactericidal activity relative to those from C57BL/6 mice, resulting from a lack of effector molecules for bacterial killing by the cells. Thus, innate immune response of macrophages is different between these mouse strains, which may affect the development of Th1 and Th2 adaptive immunity in these strains. In different experiments, we showed that C10, regarded as Th2-type chemokine in acquired immune response, is a potent monocyte chemoattractant in a sterile peritonitis model. Less

Stat3是介导IL-10抗炎特性的转录因子。为了了解Stat3在炎症中的作用，在巨噬细胞和中性粒细胞中靶向破坏Stat3的小鼠死于脓毒性腹膜炎。与对照组小鼠相比，这些小鼠表现出过度的局部和全身炎症，这一事件伴随着多种细胞因子水平的大幅增加。Stat3缺乏小鼠的肝和肾损伤明显加重。此外，小鼠在腹腔内接种活菌恢复后表现出更高的致死率。在体外，当细胞被合成脂肽、巨噬细胞激活脂肽-2（MALP-2）和LPS刺激时，炎症细胞因子的产生显著增加。因此，巨噬细胞/中性粒细胞特异性Stat3在调节与全身性炎症相关的多器官衰竭中至关重要。为了进一步了解Stat3在炎症中的作用，我们进行了进一步的实验。为此，在巨噬细胞和中性粒细胞中缺乏Stat3的小鼠腹腔注射巯基乙酸酯，并研究随后的炎症反应。我们获得的证据表明，Stat3在常驻巨噬细胞中表达，而不是其他细胞类型，在炎症反应的调节中发挥核心作用。常驻巨噬细胞在触发炎症中很重要，但同呼吸的细胞似乎通过Stat3信号通路控制炎症。C57BL/6和BALB/c小鼠分别是典型的Th1型和th2型小鼠品系。我们试图表征这些小鼠品系巨噬细胞的先天免疫反应。我们证明了来自BALB/c小鼠的巨噬细胞相对于来自C57BL/6小鼠的巨噬细胞显示出受损的杀菌活性，这是由于缺乏细胞杀死细菌的效应分子。因此，巨噬细胞的先天免疫反应在这些小鼠品系之间是不同的，这可能会影响这些品系中Th1和Th2适应性免疫的发展。在不同的实验中，我们发现C10在获得性免疫反应中被认为是th2型趋化因子，在无菌腹膜炎模型中是一种有效的单核细胞趋化剂。少