Abstract
IL-18 is an important cytokine for both innate and adaptive immunity. NK T cells and Th1 cells depend on IL-18 for their divergent functions. The IL-18R, IL-1R, and mammalian Toll-like receptors (TLRs) share homologous intracellular domains known as the TLR/IL-1R/plant R domain. Previously, we reported that IL-1R-associated kinase (IRAK)-4 plays a critical role in IL-1R and TLR signaling cascades and is essential for the innate immune response. Because TLR/IL-1R/plant R-containing receptors mediate signal transduction in a similar fashion, we investigated the role of IRAK-4 in IL-18R signaling. In this study, we show that IL-18-induced responses such as NK cell activity, Th1 IFN-gamma production, and Th1 cell proliferation are severely impaired in IRAK-4-deficient mice. IRAK-4(-/-) Th1 cells also do not exhibit NF-kappaB activation or IkappaB degradation in response to IL-18. Moreover, AP-1 activation which is triggered by c-Jun N-terminal kinase activation is also completely inhibited in IRAK-4(-/-) Th1 cells. These results suggest that IRAK-4 is an essential component of the IL-18 signaling cascade.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Division / genetics
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Cell Division / immunology
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Cells, Cultured
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Cytotoxicity, Immunologic / genetics
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Interferon-gamma / biosynthesis
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Interleukin-1 Receptor-Associated Kinases
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Interleukin-18 / metabolism
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Interleukin-18 / physiology*
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Interleukin-18 Receptor alpha Subunit
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Killer Cells, Natural / enzymology*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Mice
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Mice, Knockout
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Phosphotransferases (Alcohol Group Acceptor) / deficiency
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / physiology*
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin / genetics
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Receptors, Interleukin-1 / metabolism*
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Receptors, Interleukin-18
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Signal Transduction / genetics
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Signal Transduction / immunology
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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Th1 Cells / cytology
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Th1 Cells / enzymology*
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Th1 Cells / immunology*
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Th1 Cells / metabolism
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Th2 Cells / cytology
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Th2 Cells / enzymology
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Th2 Cells / immunology
Substances
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Il18r1 protein, mouse
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Interleukin-18
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Interleukin-18 Receptor alpha Subunit
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Receptors, Interleukin
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Receptors, Interleukin-1
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Receptors, Interleukin-18
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Interferon-gamma
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Phosphotransferases (Alcohol Group Acceptor)
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Interleukin-1 Receptor-Associated Kinases
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Irak4 protein, mouse