title: Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program.
abstract: The recognition of microbial components by Toll-like receptors (TLRs) initiates signal transduction pathways, which trigger the expression of a series of target genes. It has been reported that TLR signaling is enhanced by cytokines such as IFN-gamma, but the mechanisms underlying this enhancement remain unclear. The MyD88 adaptor, which is essential for signaling by many TLRs, recruits members of the IFN regulatory factor (IRF) family of transcription factors, such as IRF5 and IRF7, to evoke the activation of TLR target genes. In this study we demonstrate that IRF1, which is induced by IFN-gamma, also interacts with and is activated by MyD88 upon TLR activation. We provide evidence that MyD88-associated IRF1 migrates into the nucleus more efficiently than non-MyD88-associated IRF1 and that this IRF1 selectively participates in the TLR-dependent gene induction program. The critical role of MyD88-dependent "IRF1 licensing" is underscored by the observation that the induction of a specific gene subset downstream of the TLR-MyD88 pathway, such as IFN-beta, inducible NO synthase, and IL-12p35, are impaired in Irf1-deficient cells. Thus, our present study places IRF1 as an additional member participating in MyD88 signaling and provides a mechanistic insight into the enhancement of the TLR-dependent gene induction program by IFN-gamma.
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: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujita
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Shinya
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Xinshou
authors.initials: X
authors.lastname: Ouyang
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shinohara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D007371:Interferon-gamma