EVI1 Acts as an Inducible Negative-Feedback Regulator of NF-kappa B by Inhibiting p65 Acetylation

Inflammation is a hallmark of many important human diseases. Appropriate inflammation is critical for host defense; however, an overactive response is detrimental to the host. Thus, inflammation must be tightly regulated. The molecular mechanisms underlying the tight regulation of inflammation remain largely unknown. Ecotropic viral integration site 1 (EVI1), a proto-oncogene and zinc finger transcription factor, plays important roles in normal development and leukemogenesis. However, its role in regulating NF-kappa B-dependent inflammation remains unknown. In this article, we show that EVI1 negatively regulates nontypeable Haemophilus influenzae-and TNF-alpha-induced NF-kappa B-dependent inflammation in vitro and in vivo. EVI1 directly binds to the NF-kappa B p65 subunit and inhibits its acetylation at lysine 310, thereby inhibiting its DNA-binding activity. Moreover, expression of EVI1 itself is induced by nontypeable Haemophilus influenzae and TNF-alpha in an NF-kappa B-dependent manner, thereby unveiling a novel inducible negative feedback loop to tightly control NF-kappa B-dependent inflammation. Thus, our study provides important insights into the novel role for EVI1 in negatively regulating NF-kappa B-dependent inflammation, and it may also shed light on the future development of novel anti-inflammatory strategies. The Journal of Immunology, 2012, 188: 6371-6380.