title: IRF5:RelA interaction targets inflammatory genes in macrophages.
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.
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Saliba
authors.affiliation: CGAT, MRC Functional Genomics Unit, University of Oxford, South Parks Road, Oxford OX13PT, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heger
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK.
authors.forename: Hayley L
authors.initials: HL
authors.lastname: Eames
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Spyros
authors.initials: S
authors.lastname: Oikonomopoulos
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Teixeira
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK.
authors.forename: Katrina
authors.initials: K
authors.lastname: Blazek
authors.affiliation: Institute for Genetics, University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne 50931, Germany.
authors.forename: Ariadne
authors.initials: A
authors.lastname: Androulidaki
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wong
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK.
authors.forename: Fui G
authors.initials: FG
authors.lastname: Goh
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK.
authors.forename: Miriam
authors.initials: M
authors.lastname: Weiss
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Byrne
authors.affiliation: Institute for Genetics, University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne 50931, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UK. Electronic address: irina.udalova@kennedy.ox.ac.uk.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Udalova
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016678:Genome; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D020218:Response Elements; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA