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

信号换能器和转录激活器（Stat）4和Stat6分别是提供1型和2型响应的转录因子。在这里，我们探讨了Stat4和Stat6在脓毒性腹膜炎先天免疫中的作用。与野生型（WT）小鼠相比，Stat4^<-/->和Stat6^<-/->小鼠对致死率具有抗性。在机制水平上，Stat6^<-/->小鼠的细菌水平远低于WT小鼠，这与腹膜IL-12、TNFα、巨噬细胞衍生趋化因子（MDC）和C10水平增加有关，已知这些水平可增强细菌清除。在Stat4^<-/->小鼠中，脓毒症期间的肝脏炎症和损伤明显改善，但不影响局部反应。该事件与肝脏IL-10和IL-13水平升高有关，而MIP-2和KC水平降低。Stat4^<-/->小鼠脓毒症诱导的肾损伤也被消除，同时伴有肾脏MIP-2和KC水平降低，但IL-10和IL-13水平未改变。因此，Stat6^<-/->和Stat4^<-/->小鼠似乎分别通过平衡细胞因子反应增强局部细菌清除和调节全身器官损伤来抵抗脓毒性腹膜炎。这些结果清楚地强调了局部1型和全身2型细胞因子反应在脓毒症期间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在脓毒症期间胸腺细胞凋亡中的作用正在研究中。

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.