Abstract
Bone marrow-derived plasmacytoid dendritic cells (pDCs) from IL-1R-associated kinase (IRAK)2-deficient mice produced more IFNs than did wild-type pDCs upon stimulation with the TLR9 ligand CpG. Furthermore, in CpG-stimulated IRAK2-deficient pDCs there was increased nuclear translocation of IFN regulatory factor 7, the key transcription factor for IFN gene transcription in these cells. In IRAK2-deficient macrophages, enhanced NF-κB activation and increased expression of CpG-induced genes were detected within 2 h after treatment. However, at later times, NF-κB activation was decreased and, in contrast to the results with IFN, there was less secretion of other proinflammatory cytokines (such as TNF-α) and chemokines in CpG-stimulated IRAK2-deficient pDCs and macrophages. Therefore, although IRAK2 is a negative regulator of TLR9-mediated IFN production through its modulation of the transcriptional activity of IFN regulatory factor 7, it is also a positive regulator of TLR9-mediated proinflammatory cytokine and chemokine production at some level subsequent to transcription.
MeSH terms
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Animals
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Cells, Cultured
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CpG Islands / immunology
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis*
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Cytokines / physiology
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Down-Regulation / immunology
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Herpesviridae Infections / enzymology
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Herpesviridae Infections / immunology
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Herpesviridae Infections / pathology
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Inflammation Mediators / antagonists & inhibitors
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Inflammation Mediators / metabolism*
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Inflammation Mediators / physiology
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Interferon Regulatory Factor-7 / antagonists & inhibitors
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Interferon Regulatory Factor-7 / physiology
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Interferon Type I / antagonists & inhibitors
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Interferon Type I / biosynthesis*
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Interferon-alpha
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Interferon-beta / antagonists & inhibitors
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Interferon-beta / biosynthesis*
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Interleukin-1 Receptor-Associated Kinases / deficiency
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Interleukin-1 Receptor-Associated Kinases / physiology*
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Ligands
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Mice
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Mice, Knockout
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Recombinant Proteins
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Rhadinovirus / immunology
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Toll-Like Receptor 9 / metabolism
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Toll-Like Receptor 9 / physiology*
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Tumor Virus Infections / enzymology
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Tumor Virus Infections / immunology
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Tumor Virus Infections / pathology
Substances
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Cytokines
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Inflammation Mediators
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Interferon Regulatory Factor-7
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Interferon Type I
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Interferon-alpha
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Irf7 protein, mouse
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Ligands
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Recombinant Proteins
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Tlr9 protein, mouse
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Toll-Like Receptor 9
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interferon alpha 4A
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Interferon-beta
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Interleukin-1 Receptor-Associated Kinases