Journal Article

Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4

Suzuki, Shinobu, Wakeham, Andrew, Ohashi, Pamela S., Wada, Teiji, Yeh, Wen-Chen, Li, Shyun, Wesche, Holger, Suzuki, Nobutaka, Takada, Hidetoshi, Mak, Tak W., Itie, Annick, Penninger, Josef M., Mirtsos, Christine, Millar, Douglas G., Duncan, Gordon S.

2002

Overview

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 1 , 2 , 3 . Intracellular signalling mechanisms mediated by TIRs are similar 4 , 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) 11 and two homologous proteins, IRAK-2 (ref. 12 ) and IRAK-M 13 . 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 14 , 15 . Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein 16 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Arenaviridae Infections - immunology / Arenaviridae Infections - metabolism / B-Lymphocytes - drug effects / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Cells / Cells, Cultured / Drosophila / Drosophila Proteins / Gene Deletion / Genes / Humanities and Social Sciences / Immunity (Disease) / Immunity, Innate - immunology / Interferon-gamma - analysis / Interleukin-1 - biosynthesis / Interleukin-1 - pharmacology / Interleukin-1 Receptor-Associated Kinases / Interleukin-6 - biosynthesis / IRAK-4 protein / JNK Mitogen-Activated Protein Kinases / Killer Cells, Natural - drug effects / Killer Cells, Natural - immunology / letter / Ligands / Lipopolysaccharides - pharmacology / Lymphocytic choriomeningitis virus - physiology / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Membrane Glycoproteins - metabolism / Mice / Mitogen-Activated Protein Kinases - metabolism / Molecules / multidisciplinary / NF-kappa B - metabolism / Nitric Oxide - metabolism / p38 Mitogen-Activated Protein Kinases / Protein Kinases - deficiency / Protein Kinases - genetics / Protein Kinases - metabolism / Proteins / Receptors, Cell Surface - metabolism / Receptors, Interleukin-1 - metabolism / Rodents / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Staphylococcal Infections - immunology / Staphylococcal Infections - metabolism / Staphylococcus aureus - physiology / Toll-Like Receptors / Tumor Necrosis Factor-alpha - biosynthesis / Tumor Necrosis Factor-alpha - pharmacology