title: Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4.
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.
authors.affiliation: Amgen Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Suzuki
authors.forename: Shinobu
authors.initials: S
authors.lastname: Suzuki
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Duncan
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Millar
authors.forename: Teiji
authors.initials: T
authors.lastname: Wada
authors.forename: Christine
authors.initials: C
authors.lastname: Mirtsos
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Annick
authors.initials: A
authors.lastname: Itie
authors.forename: Shyun
authors.initials: S
authors.lastname: Li
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Holger
authors.initials: H
authors.lastname: Wesche
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D029721:Drosophila Proteins; D017353:Gene Deletion; D007113:Immunity, Innate / Q000276:immunology; D007371:Interferon-gamma / Q000032:analysis; D007375:Interleukin-1 / Q000096:biosynthesis / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D015850:Interleukin-6 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism; D013211:Staphylococcus aureus / Q000502:physiology; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D029721:Drosophila Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases