Abstract
Interleukin (IL)-18 is functionally similar to IL-12 in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity but is related to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor-associated kinase (IRAK) to the receptor and activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-kappaB. The role of IRAK in IL-18-induced responses was studied in IRAK-deficient mice. Significant defects in JNK induction and partial impairment in NF-kappaB activation were found in IRAK-deficient Th1 cells, resulting in a dramatic decrease in interferon (IFN)-gamma mRNA expression. In vivo Th1 response to Propionibacterium acnes and lipopolysaccharide in IFN-gamma production and induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-gamma production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays an important role in IL-18-induced signaling and function.
Publication types
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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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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Chimera
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Crosses, Genetic
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Cytomegalovirus Infections / immunology
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Cytotoxicity, Immunologic / drug effects
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Depression, Chemical
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Enzyme Activation / drug effects
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Enzyme Induction / drug effects
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Female
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Gene Expression Regulation / drug effects
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interleukin-1 Receptor-Associated Kinases
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Interleukin-18 / pharmacology*
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Interleukin-18 Receptor alpha Subunit
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics
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JNK Mitogen-Activated Protein Kinases
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Killer Cells, Natural / immunology*
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Lipopolysaccharides / immunology
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Lymphocyte Activation / drug effects
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinases*
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NF-kappa B / metabolism
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Propionibacterium acnes / immunology
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Protein Kinases / deficiency*
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Protein Kinases / genetics
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Protein Kinases / physiology
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Receptors, Interleukin / physiology
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Receptors, Interleukin-18
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Signal Transduction / physiology*
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Th1 Cells / cytology
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Th1 Cells / immunology*
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Th2 Cells / cytology
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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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Lipopolysaccharides
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NF-kappa B
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Receptors, Interleukin
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Receptors, Interleukin-18
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Interleukin-4
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Interferon-gamma
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Protein Kinases
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Interleukin-1 Receptor-Associated Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases