Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / metabolism
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Cell Line
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DNA-Binding Proteins / metabolism*
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Dendritic Cells / physiology*
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Gene Expression Regulation / genetics
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Gene Expression Regulation / physiology
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Humans
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Interferon Regulatory Factor-7
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Interferon-alpha / biosynthesis*
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Interleukin-1 Receptor-Associated Kinases
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinases / metabolism
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Myeloid Differentiation Factor 88
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NF-kappa B / metabolism
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Plasma Cells / physiology
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / metabolism
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Receptors, Tumor Necrosis Factor / metabolism
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Signal Transduction / genetics
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Signal Transduction / physiology*
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TNF Receptor-Associated Factor 6 / metabolism
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Toll-Like Receptor 7
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Toll-Like Receptor 9
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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DNA-Binding Proteins
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IRF7 protein, human
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Interferon Regulatory Factor-7
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Interferon-alpha
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Irf7 protein, mouse
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MYD88 protein, human
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Tumor Necrosis Factor
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TLR9 protein, human
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TNF Receptor-Associated Factor 6
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Tlr7 protein, mouse
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Tlr9 protein, mouse
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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Protein Kinases
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Interleukin-1 Receptor-Associated Kinases
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Mitogen-Activated Protein Kinases