The zinc finger protein and transcriptional repressor Gfi1 as a regulator of the innate immune response

Gfi1 is a transcriptional repressor with a molecular weight between 47 and 55 kDa. The protein has six C-terminal C2H2-type zinc finger domains and a characteristic stretch of 20 amino acids, called the SNAG-domain, at its N-terminus. Expression of Gfi1 ranges from the hematopoietic and lymphoid system to sensory epithelia, lung and parts of the CNS. Gene knockout studies revealed that Gfi1 is essential for the development of granulocytes and plays a role in macrophage-dependent cytokine production, indicating that this protein shares the responsibility for different lines of defense against pathogens. Strikingly, Gfi1-deficient mice are highly sensitive to both endotoxin and bacterial infections and die rapidly after an experimental application of endotoxin or induction of infection with symptoms of septic shock. This sensitivity is mediated by an overproduction of tumor necrosis factor (TNF) and other inflammatory cytokines. The lung could be identified as the principal organ in which the accelerated inflammatory reactions take place in challenged Gfi1-deficient mice. Several lines of experimental evidence support a role of Gfi1 as a regulator of the Toll-like receptor (TLR) pathways, and, in general, as an essential modulator preventing an overshooting of the inflammatory response.