Abstract
Interferon regulatory factors (IRFs) are critical components of virus-induced immune activation and type I interferon regulation. IRF3 and IRF7 are activated in response to a variety of viruses or after engagement of Toll-like receptor (TLR) 3 and TLR4 by double-stranded RNA and lipopolysaccharide, respectively. The activation of IRF5, is much more restricted. Here we show that in contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway but is activated by TLR7 or TLR8 signaling. We also demonstrate that MyD88, interleukin 1 receptor-associated kinase 1, and tumor necrosis factor receptor-associated factor 6 are required for the activation of IRF5 and IRF7 in the TLR7 signaling pathway. Moreover, ectopic expression of IRF5 enabled type I interferon production in response to TLR7 signaling, whereas knockdown of IRF5 by small interfering RNA reduced type I interferon induction in response to the TLR7 ligand, R-848. IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation / metabolism
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Biological Assay
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Cell Line
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DNA-Binding Proteins / metabolism*
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DNA-Binding Proteins / physiology*
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Dose-Response Relationship, Drug
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Electroporation
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Genes, Reporter
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Glutathione Transferase / metabolism
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Humans
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Interferon Regulatory Factors
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Interferon Type I / metabolism
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Ligands
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Lipopolysaccharides / metabolism
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Membrane Glycoproteins / metabolism*
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Microscopy, Confocal
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Models, Biological
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Myeloid Differentiation Factor 88
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Phosphorylation
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RNA Interference
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RNA, Double-Stranded / metabolism
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RNA, Small Interfering / metabolism
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / metabolism
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Time Factors
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptor 7
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Toll-Like Receptor 8
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Toll-Like Receptors
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transfection
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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IRF3 protein, human
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IRF5 protein, human
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IRF7 protein, human
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Interferon Regulatory Factors
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Interferon Type I
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Ligands
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Lipopolysaccharides
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MYD88 protein, human
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Membrane Glycoproteins
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Myeloid Differentiation Factor 88
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RNA, Double-Stranded
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RNA, Small Interfering
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Receptors, Cell Surface
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Receptors, Immunologic
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Recombinant Fusion Proteins
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TLR3 protein, human
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TLR4 protein, human
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TLR7 protein, human
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TLR8 protein, human
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptor 7
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Toll-Like Receptor 8
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Toll-Like Receptors
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Transcription Factors
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Glutathione Transferase