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

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.

Pubmed ID: 11923871

Authors

  • Suzuki N
  • Suzuki S
  • Duncan GS
  • Millar DG
  • Wada T
  • Mirtsos C
  • Takada H
  • Wakeham A
  • Itie A
  • Li S
  • Penninger JM
  • Wesche H
  • Ohashi PS
  • Mak TW
  • Yeh WC

Journal

Nature

Publication Data

April 18, 2002

Associated Grants

None

Mesh Terms

  • Animals
  • Arenaviridae Infections
  • B-Lymphocytes
  • Cells, Cultured
  • Drosophila Proteins
  • Gene Deletion
  • Immunity, Innate
  • Interferon-gamma
  • Interleukin-1
  • Interleukin-1 Receptor-Associated Kinases
  • Interleukin-6
  • JNK Mitogen-Activated Protein Kinases
  • Killer Cells, Natural
  • Ligands
  • Lipopolysaccharides
  • Lymphocytic choriomeningitis virus
  • Macrophages
  • Membrane Glycoproteins
  • Mice
  • Mitogen-Activated Protein Kinases
  • NF-kappa B
  • Nitric Oxide
  • Protein Kinases
  • Receptors, Cell Surface
  • Receptors, Interleukin-1
  • Signal Transduction
  • Staphylococcal Infections
  • Staphylococcus aureus
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases