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J Immunol. 2012 Jun 15;188(12):6371-80. doi: 10.4049/jimmunol.1103527. Epub 2012 May 11.

EVI1 acts as an inducible negative-feedback regulator of NF-κB by inhibiting p65 acetylation.

Author information

1
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.

Abstract

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-κB-dependent inflammation remains unknown. In this article, we show that EVI1 negatively regulates nontypeable Haemophilus influenzae- and TNF-α-induced NF-κB-dependent inflammation in vitro and in vivo. EVI1 directly binds to the NF-κB 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-α in an NF-κB-dependent manner, thereby unveiling a novel inducible negative feedback loop to tightly control NF-κB-dependent inflammation. Thus, our study provides important insights into the novel role for EVI1 in negatively regulating NF-κB-dependent inflammation, and it may also shed light on the future development of novel anti-inflammatory strategies.

PMID:
22581859
PMCID:
PMC3370108
DOI:
10.4049/jimmunol.1103527
[Indexed for MEDLINE]
Free PMC Article

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