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Role of Th1/Th2 cytokines and their regulation in a murine model of septic peritonitis

Th1/Th2细胞因子在脓毒症腹膜炎小鼠模型中的作用及其调控

基本信息

批准号：
13670222
负责人：
MATSUKAWA Akihiro
金额：
$ 2.24万
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：
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-13670222/
关键词：
Sepsis Innate immunity Th1 Th2 cytokine SIRS Stat4 Stat6 Chemokine 全身性炎症反応症候群 STAT4 STAT6

项目摘要

Signal transducer and activator of transcription (Stat)4 and Stat6 are transcription factors that provide type-1 and type-2 response, respectively. Here, we explored the role of Stat4 and Stat6 in innate immunity during septic peritonitis. Stat4^<-/-> and Stat6^<-/-> mice were resistant to the lethality, as compared to wild-type (WT) mice. At the mechanistic level, bacterial levels in Stat6^<-/-> mice were much lower than WT mice, which was associated with increased peritoneal levels of IL-12, TNFα, macrophage derived chemokine (MDC) and C10, known to enhance bacterial clearance. In Stat4^<-/-> mice, hepatic inflammation and injury during sepsis were significantly ameliorated without affecting local responses. This event was associated with increased hepatic levels of IL-10 and IL-13, while decreasing those of MIP-2 and KC. Sepsis-induced renal injury was also abrogated in Stat4^<-/-> mice, which was accompanied by decreased renal levels of MIP-2 and KC without altering IL-10 and IL-13 levels. Thus, Stat6^<-/-> and Stat4^<-/-> mice appeared to be resistant to septic peritonitis by enhancing local bacterial clearance and modulating systemic organ damage, respectively, via balancing cytokine responses. These results clearly highlight an important role of local type-1 and systemic type-2 cytokine response in protective immunity during sepsis, which can be regulated by Stat proteins. We are currently investigating the involvement of Stat proteins in the production of MDC and C10. In addition, the contribution of Stat4 and Stat6 in thymic apoptosis during sepsis is under investigation.

信号转导和转录激活因子(Stat)4和Stat6分别是提供1型和2型反应的转录因子。在这里，我们探讨了STAT4和STAT6在感染性腹膜炎的先天免疫中的作用。与野生型(WT)小鼠相比，STAT4^&lt；-/-&gt；和Stat6^&lt；-/-&gt；小鼠对致死性具有抵抗力。在机制水平上，STAT6^-lt；-/-&gt；小鼠的细菌水平比WT小鼠低得多，这与腹膜IL-12、肿瘤坏死因子α、巨噬细胞衍生趋化因子和C10水平的增加有关，众所周知，这有助于提高细菌的清除能力。在STAT4^-lt；-/-&gt；小鼠中，脓毒症期间的肝脏炎症和损伤显著改善，而不影响局部反应。这一事件与肝脏IL-10和IL-13水平升高，而MIP-2和KC水平下降有关。STAT4-lt；-/-&gt；小鼠脓毒症所致的肾损伤也被消除，伴随着肾脏MIP-2和KC水平的降低，但不改变IL-10和IL-13水平。因此，STAT6^&lt；-/-&gt；和STAT4^&lt；-/-&gt；小鼠似乎分别通过增强局部细菌清除和通过平衡细胞因子反应调节全身器官损伤来抵抗感染性腹膜炎。这些结果清楚地强调了局部1型和全身型2型细胞因子反应在脓毒症保护性免疫中的重要作用，这可以由Stat蛋白调节。我们目前正在研究Stat蛋白在MDC和C10的产生中的作用。此外，STAT4和STAT6在脓毒症时胸腺细胞凋亡中的作用正在研究中。