title: Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors.
abstract: The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity. All TLRs use the adaptor MyD88 for signalling, but the mechanisms underlying the MyD88-mediated gene induction programme are as yet not fully understood. Here, we demonstrate that the transcription factor IRF-5 is generally involved downstream of the TLR-MyD88 signalling pathway for gene induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 gene (Irf5-/- mice), the induction of these cytokines by various TLR ligands is severely impaired, whereas interferon-alpha induction is normal. We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6, and that TLR activation results in the nuclear translocation of IRF-5 to activate cytokine gene transcription. Consistently, Irf5-/- mice show resistance to lethal shock induced by either unmethylated DNA or lipopolysaccharide, which correlates with a marked decrease in the serum levels of proinflammatory cytokines. Thus, our study identifies IRF-5 as a new, principal downstream regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.forename: Gordon
authors.initials: G
authors.lastname: Duncan
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Mizutani
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Kano
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D014157:Transcription Factors