Analysis of signal transduction pathway in innate immunity during sepsis

STAT3是一种转录因子，介导IL-10的抗炎作用。为了了解STAT3在炎症中的作用，将巨噬细胞和中性粒细胞中的STAT3定向干扰的小鼠死于感染性腹膜炎。与对照小鼠相比，小鼠表现出过度的局部和全身炎症，伴随着多种细胞因子水平的大幅增加。在STAT3缺乏的小鼠中，肝和肾脏的损伤显著加重。此外，在腹腔内接种恢复的活细菌后，小鼠的致死率增加。在体外，当合成脂肽、巨噬细胞激活脂肽-2(MALP-2)和内毒素刺激细胞时，炎症细胞因子的产生显著增加。因此，巨噬细胞/中性粒细胞特异的STAT3在调节与全身炎症相关的多器官衰竭中至关重要。进一步进行了实验以了解Pr…STAT3在炎症中的作用更明显。为此，在巨噬细胞和中性粒细胞中缺乏STAT3的小鼠被注射硫代乙酸酯，随后的炎症反应被研究。我们获得的证据表明，STAT3在常驻巨噬细胞中表达，而不是其他类型的细胞，在炎症反应的调节中发挥核心作用。驻留巨噬细胞在引发炎症方面很重要，但同时存在的巨噬细胞似乎通过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。我们试图表征这些小鼠品系的巨噬细胞的先天免疫反应。我们证明，BALB/c小鼠的巨噬细胞相对于C57BL/6小鼠的巨噬细胞显示出减弱的杀菌活性，这是由于缺乏细胞杀菌的效应分子所致。因此，不同品系的小鼠巨噬细胞的天然免疫反应不同，这可能会影响这些品系的Th1和Th2获得性免疫的发展。在不同的实验中，我们证明了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强大的单核细胞趋化因子。较少

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