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

Gfi-1是一种55 kD的核锌指蛋白，迄今为止一直被认为仅作为T细胞特异性转录抑制因子。然而，我们最近发现，这种蛋白质也在粒细胞和LPS处理的巨噬细胞中表达，这暗示了这种蛋白质在先天免疫系统中的作用。Gfi-1缺陷小鼠的表型支持这种作用，因为这些动物在3个月龄内过早死亡，症状类似于败血性休克。此外，Gfi-1缺失小鼠具有严重的中性粒细胞减少症，并产生高度升高水平的炎性细胞因子如TNF和IL-10。使用组合突变小鼠，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全身反应，铜绿假单胞菌是临床上最相关的机会性细菌之一。此外，我们希望探索负责LPS处理或铜绿假单胞菌感染后原代小鼠巨噬细胞中Gfi-1表达活化的信号转导途径。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.