Format

Send to

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

IRF5:RelA interaction targets inflammatory genes in macrophages.

Author information

1
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK.
2
CGAT, MRC Functional Genomics Unit, University of Oxford, South Parks Road, Oxford OX13PT, UK.
3
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
4
Institute for Genetics, University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne 50931, Germany.
5
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK. Electronic address: irina.udalova@kennedy.ox.ac.uk.

Abstract

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.

PMID:
25159141
PMCID:
PMC4471814
DOI:
10.1016/j.celrep.2014.07.034
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center