title: Critical role of IkappaB Kinase alpha in TLR7/9-induced type I IFN production by conventional dendritic cells.
abstract: A plasmacytoid dendritic cell (DC) can produce large amounts of type I IFNs after sensing nucleic acids through TLR7 and TLR9. IkappaB kinase alpha (IKKalpha) is critically involved in this type I IFN production through its interaction with IFN regulatory factor-7. In response to TLR7/9 signaling, conventional DCs can also produce IFN-beta but not IFN-alpha in a type I IFN-independent manner. In this study, we showed that IKKalpha was required for production of IFN-beta, but not of proinflammatory cytokines, by TLR7/9-stimulated conventional DCs. Importantly, IKKalpha was dispensable for IFN-beta gene upregulation by TLR4 signaling. Biochemical analyses indicated that IKKalpha exerted its effects through its interaction with IFN regulatory factor-1. Furthermore, IKKalpha was involved in TLR9-induced type I IFN-independent IFN-beta production in vivo. Our results show that IKKalpha is a unique molecule involved in TLR7/9-MyD88-dependent type I IFN production through DC subset-specific mechanisms.
authors.affiliation: Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Graduate School of Nanobioscience, Yokohama City University, Yokohama, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Izumi
authors.initials: I
authors.lastname: Sasaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yano
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamazaki
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yasui
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D051550:I-kappa B Kinase / Q000276:immunology*; D047468:Immunoprecipitation; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D016899:Interferon-beta; D051550:I-kappa B Kinase