Gfi1 in innate immunity: a downstream effector of Toll like receptor signaling and a novel regulator of endotoxin tolerance

GFI-1是一个55kD的核锌指蛋白，到目前为止一直被认为只作为T细胞特异性转录抑制因子发挥作用。然而，我们最近发现，这种蛋白在粒细胞和脂多糖处理的巨噬细胞中也有表达，这暗示了这种蛋白在先天性免疫系统中的作用。GFI-1缺陷小鼠的表型支持这种作用，因为这些动物在3个月内过早死亡，症状类似感染性休克。此外，GFI-1基因缺失的小鼠有严重的中性粒细胞减少，并产生高度升高的炎性细胞因子，如肿瘤坏死因子和白介素10。利用组合突变小鼠，我们计划确定GFI-1如何调节对内毒素或铜绿假单胞菌感染的系统反应，铜绿假单胞菌是临床上最相关的机会细菌之一。此外，我们希望探索在脂多糖处理或铜绿假单胞菌感染时，在原代小鼠巨噬细胞中激活GFI-1表达的信号转导途径。最后，我们的目标是确定在细菌感染的巨噬细胞中受GFI-1调控的效应基因和信号通路。

Gfi-1 is a 55kD nuclear zinc finger protein which until now has been considered to act solely as a T-cell specific transcriptional repressor. However, we have recently discovered that this protein is also expressed in granulocytes and LPS treated macrophages which implicated a role of this protein in the innate immune system. The phenotype of Gfi-1 deficient mice supported such a role since these animals die prematurely with symptoms similar to septic shock within 3 months of age. Moreover Gfi-1 null mice have a severe neutropenia and produce highly elevated levels of inflammatory cytokines as TNF and IL-10. Using combinatorial mutant mice we plan to determine how Gfi-1 modulates the systemic response to endotoxins or an infection with P. aeruginosa, which is one of the clinically most relevant opportunistic bacteria. In addition, we wish to explore the signal transduction pathways that are responsible for the activation of Gfi-1 expression in primary murine macrophages upon LPS treatment or P. aeruginosa infection. Finally, we aim to determine the effector genes and signaling pathways that are regulated by Gfi-1 in bacterially infected macrophages.