Abstract
Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Intracellular signalling mechanisms mediated by TIRs are similar, with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arenaviridae Infections / immunology
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Arenaviridae Infections / metabolism
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Cells, Cultured
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Drosophila Proteins*
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Gene Deletion
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Immunity, Innate / immunology
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Interferon-gamma / analysis
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Interleukin-1 / biosynthesis
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Interleukin-1 / pharmacology
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Interleukin-1 Receptor-Associated Kinases
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Interleukin-6 / biosynthesis
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JNK Mitogen-Activated Protein Kinases
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Ligands
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Lipopolysaccharides / pharmacology
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Lymphocytic choriomeningitis virus / physiology
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Membrane Glycoproteins / metabolism*
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / metabolism
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Nitric Oxide / metabolism
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Protein Kinases / deficiency*
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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, Interleukin-1 / metabolism*
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Signal Transduction* / drug effects
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Staphylococcal Infections / immunology
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Staphylococcal Infections / metabolism
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Staphylococcus aureus / physiology
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / pharmacology
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p38 Mitogen-Activated Protein Kinases
Substances
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Drosophila Proteins
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Interleukin-1
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Interleukin-6
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Ligands
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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Receptors, Cell Surface
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Receptors, Interleukin-1
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Nitric Oxide
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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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Irak3 protein, mouse
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases