IRF5:RelA interaction targets inflammatory genes in macrophages

Cell Rep. 2014 Sep 11;8(5):1308-17. doi: 10.1016/j.celrep.2014.07.034. Epub 2014 Aug 21.


Interferon Regulatory Factor 5 (IRF5) plays a major role in setting up an inflammatory macrophage phenotype, but the molecular basis of its transcriptional activity is not fully understood. In this study, we conduct a comprehensive genome-wide analysis of IRF5 recruitment in macrophages stimulated with bacterial lipopolysaccharide and discover that IRF5 binds to regulatory elements of highly transcribed genes. Analysis of protein:DNA microarrays demonstrates that IRF5 recognizes the canonical IRF-binding (interferon-stimulated response element [ISRE]) motif in vitro. However, IRF5 binding in vivo appears to rely on its interactions with other proteins. IRF5 binds to a noncanonical composite PU.1:ISRE motif, and its recruitment is aided by RelA. Global gene expression analysis in macrophages deficient in IRF5 and RelA highlights the direct role of the RelA:IRF5 cistrome in regulation of a subset of key inflammatory genes. We map the RelA:IRF5 interaction domain and suggest that interfering with it would offer selective targeting of macrophage inflammatory activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Genome
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Macrophage Activation / genetics
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Response Elements
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcriptional Activation


  • Interferon Regulatory Factors
  • Irf5 protein, mouse
  • Rela protein, mouse
  • Transcription Factor RelA