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

Nobutaka Suzuki, Shinobu Suzuki, Gordon S. Duncan, Douglas G. Millar, Teiji Wada, Christine Mirtsos, Hidetoshi Takada, Andrew Wakeham, Annick Itie, Shyun Li, Josef M. Penninger, Holger Wesche, Pamela S. Ohashi, Tak W. Mak and Wen-Chen Yeh
Additional contact information
Nobutaka Suzuki: University of Toronto
Shinobu Suzuki: University of Toronto
Gordon S. Duncan: University of Toronto
Douglas G. Millar: University of Toronto
Teiji Wada: University of Toronto
Christine Mirtsos: University of Toronto
Hidetoshi Takada: University of Toronto
Andrew Wakeham: University of Toronto
Annick Itie: University of Toronto
Shyun Li: Tularik Incorporation
Josef M. Penninger: University of Toronto
Holger Wesche: Tularik Incorporation
Pamela S. Ohashi: University of Toronto
Tak W. Mak: University of Toronto
Wen-Chen Yeh: University of Toronto

Nature, 2002, vol. 416, issue 6882, 750-754

Abstract: 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) domains1,2,3. Intracellular signalling mechanisms mediated by TIRs are similar4, 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-M13. 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 signalling14,15. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein16, 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.

Date: 2002
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DOI: 10.1038/nature736

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