Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction.
Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-alpha in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-alpha production was abolished in Irak-1-deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-kappaB and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1-deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-alpha induction in pDCs.
Uematsu
Satoshi
S
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita Osaka 565-0871, Japan.
Sato
Shintaro
S
Yamamoto
Masahiro
M
Hirotani
Tomonori
T
Kato
Hiroki
H
Takeshita
Fumihiko
F
Matsuda
Michiyuki
M
Coban
Cevayir
C
Ishii
Ken J
KJ
Kawai
Taro
T
Takeuchi
Osamu
O
Akira
Shizuo
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha / Q000096:biosynthesis*; D053592:Interleukin-1 Receptor-Associated Kinases; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D010950:Plasma Cells / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; C494235:Irf7 protein, mouse; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; C495371:TLR9 protein, human; D048029:TNF Receptor-Associated Factor 6; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D020928:Mitogen-Activated Protein Kinases