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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Feedback, Physiological / physiology*
  • Haemophilus Infections / immunology
  • Haemophilus Infections / metabolism
  • Haemophilus influenzae / immunology
  • Immunoprecipitation
  • Inflammation / immunology
  • Inflammation / metabolism*
  • MDS1 and EVI1 Complex Locus Protein
  • Mice
  • Mice, Mutant Strains
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Proto-Oncogenes / immunology
  • RNA Interference
  • Real-Time Polymerase Chain Reaction
  • Transcription Factor RelA / immunology
  • Transcription Factor RelA / metabolism*
  • Transcription Factors / immunology
  • Transcription Factors / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / immunology


  • DNA-Binding Proteins
  • MDS1 and EVI1 Complex Locus Protein
  • Mecom protein, mouse
  • NF-kappa B
  • Rela protein, mouse
  • Transcription Factor RelA
  • Transcription Factors
  • Tumor Necrosis Factor-alpha