1. TLR. TLR Toll-like receptors. Toll Toll-like receptor, TLR TLR TLR TLR. type I TLR TLR. Toll

Transcription

1 54pp TLR T B TLR Toll-like receptors TLR TLR I IFN TLR T B B T Toll NF- B TEL FAX uemattsu@biken.osaka-u.ac.jp Toll Toll-like receptor, TLR TLR 1 TLR TLR type I IFN TLR TLR NK B T T B

2 Toll-like receptor TLR LRR 1IL-1R Toll/IL-1R TIR MyD88, TIRAP, TRIF, TRAM TIR TLR TLR 3 TLR MyD88 TIR TLR / IL-1 receptor associated kinase s IRAKs IRAKs TNF receptor associated factor 6 TRAF6I B kinase IKK IKK I B degradation NF- B MyD88 TNF- IL-6 MyD88 1 TLR pathogen-associated molecular patterns; PAMPs TLR 11 1 TLR4 lipopolysaccharide LPS TLR4 LPS MD-2 TLR2 TLR2 TLR1 TLR6 TLR5 DNA TLR CpG DNA DNA CpG DNA CpG CpG DNA TLR9 CpG DNA 2 TLR 2 TLR TLR IL-1R TIR Toll/IL-1RTIR MyD88, TIRAP/Mal, TRIF, TRAMTLR TIR

3 pp TLR2 TLR1 TLR6 TLR2 TLR4 LPS TLR5 TLR9 CpG DNA TLR3 dsrna TLR7 ssrna TLR TLR TLR3 TLR MyD88 TLR TLR TLR open reading frame A46R A52R IL-1R TLR TIR A46R IL-1R A52R IL-1R TLR4 NF- B A52R MyD88 2 IL-1R TLR TLR4 respiratory syncytial virus RSV TLR4 C3H/HeJ RSV mouse mammary tumor virus MMTV TLR4 B TLR4 2 2 RNA double stranded RNA: dsrna I IFN / dsrna RNA dsrna polyinosinicpolycytidylic acid poly I:C dsrna TLR3 dsrna 1 TLR3 TLR4 TLR9 TLR7 TLR9 CpG DNA plasmacytoid dendritic cell: PDCIFN- DNA herpes simplex virus-2 HSV-2 TLR9 PDC IFN- TLR9 DNA CpG

4 R-848 TLR7 TLR7 TLR7 TLR7 TLR8 RNA single starand RNA: ssrna 1 2 TLR I IFN TLR T TNF- IL-6 TLR I IFN I IFN MHC CD8T I IFN 10 1 I IFN 1 TLR I IFN I IFN TLR3 TLR4 TLR7 TLR9 4 TLR3 TLR4 IFN- 1 TLR7 TLR9 IFN- IFN- 3 TLR3 TLR4 IFN- MyD88 MyD88 TLR3 TLR TLR4 TLR3 NF- B MAPK TLR3 TLR4 MyD88 MyD88 2 TRIF 4 TRIF MyD88 NF- B TRIF MyD88 IFN- TRIF 5 TRIF TLR3 dsrna IFN- IFN IFN- IRF-3 TRIF TLR4 LPS IFN- IFN IRF-3 TRIF TLR3 TLR4 MyD88 TLR4 MyD88 TRIF TIR TRAM 6 IKKi TBK1 TLR I IFN I IFN IRF 10 IRF IRF-3 IRF-7 IFN 7 2 IRF Hiscott noncanonical IKKs TANK-binding kinase 1 TBK1 IKKi/IKK IRF-3 in vitro TBK1 IKKi IRF-3 RNAi TBK1 IKKi IRF-3 8 Maniatis TBK1 IKKi IRF-3 IFN- 9 TBK1 Newcastle disease dsrna LPS I IFN IFN TBK1 10 TBK1 Cheng TBK1 TNF- TBK1 LPS dsrna I IFN TBK1 IFN TBK1 IKKi IFN IKKi Chen TLR IFN TBK1 IFN IKKi 11 TBK1 IKKi I IFN TBK1 LPS, dsrna

5 pp TLR3 TLR4 MyD88 TLR3, TLR4 TRIF TIR TLR3 TLR4 IKKi TBK1 TRIF IRF3 IFN- IFN TLR4 MyD88 TRAM TLR7, 8, 9 PDC MyD88 IFN- IFN- MyD88/TRAF6/IRF7 IRF7

6 IFN- IFN IKKi dsrna IFN- IFN TBK1 TBK1/IKKi TLR3, 4 I IFN IRF3 TBK1 IKKi 12 TLR7 TLR9 I IFN TLR9 CpG DNA CpG DNA IL-12 classical CpG DNA A/D type CpG DNA CD11c B220 CD11c B220 IFN- plasmacytoid DC: PDC A/D type CpG DNA CD11c B220 PDC IL-12 classical CpG DNA IFN- TLR9 MyD88 13 TLR7 TLR8 PDC IFN- MyD88 TLR7, 8, 9 PDC MyD88 IFN- IRF7 MyD88 14 IRF7 IRF3 TLR type I IFN IRF3 IFN- IKK TBK1 IKKi IRF7 IFN- IRF3 IRF7 I IFN PDC IRF7 TLR7, 8, 9 IFN-IRF7 TLR7, 8, 9 IFN- MyD88 IIRF3 IRF7 MyD88 IRF7 IFN- PDC A/D type CpG DNA IRF7 MyD88 PDC IRF7 IRF7 MyD88 TRAF6 TRAF6 IRF7 TLR7, 8, 9 IFN- MyD88/TRAF6/IRF7 TLR3, 4 IFN- TRIF TRAM TIR IRF3 TLR7, 8, 9 IFN-IRF7 MyD88 IFN- IRF7 PDC IRF3 TBK1 PDC TLR9 IFN- 14 IRF7 TLR TLR TLR I IFN TLR TLR 1 Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. Jul , Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol , Kaisho T, Akira S. Regulation of dendritic cell function through toll-like receptors. Curr Mol Med , Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S. Cutting edge a novel Toll/ IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol , Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science , Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino

7 pp K, Kaisho T, Takeuchi O, Takeda K, Akira S. TRAM is specifically involved in the Toll-like receptor 4- mediated MyD88-independent signaling pathway. Nat Immunol , Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Katsuki M, Noguchi S, Tanaka N, Taniguchi T. Distinct and Essential Roles of Transcription Factors IRF-3 and IRF-7 in Response to Viruses for IFN-alpha/beta Gene Induction. Immunity 13, , Sharma S, tenoever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway. Science , NT. Liberati, KA. Fitzgerald, DH. Kim, R. Feinbaum, DT. Golenbock et al. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc Natl Acad Sci U S A , SM. McWhirter, KA. Fitzgerald, J. Rosains, DC. Rowe, DT. Golenbock et al. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci U S A , AK. Perry, EK. Chow, JB. Goodnough, WC. Yeh G. Cheng. Differential Requirement for TANK-binding Kinase-1 in Type I Interferon Responses to Toll-like Receptor Activation and Viral Infection. J. Exp. Med , Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, Kawai T, Hoshino K, Takeda K, Akira S. The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med , Hemmi H, Kaisho T, Takeda K, Akira S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol , Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O, Akira S. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol , TLR family and viral infection Satoshi Uematsu and Shizuo Akira Department of Host defense Research Institute for Microbial Diseases Osaka University 3-1 Yamadaoka, Suita, , Japan uemattsu@biken.osaka-u.ac.jp

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