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A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity.

Authors
  • Kim, Tae Whan
  • Staschke, Kirk
  • Bulek, Katarzyna
  • Yao, Jianhong
  • Peters, Kristi
  • Oh, Keun-Hee
  • Vandenburg, Yvonne
  • Xiao, Hui
  • Qian, Wen
  • Hamilton, Tom
  • Min, Booki
  • Sen, Ganes
  • Gilmour, Raymond
  • Li, Xiaoxia
Type
Published Article
Journal
The Journal of experimental medicine
Publication Date
May 14, 2007
Volume
204
Issue
5
Pages
1025–1036
Identifiers
PMID: 17470642
Source
Medline
License
Unknown

Abstract

IRAK4 is a member of IL-1 receptor (IL-1R)-associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)-mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase-inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinflammatory cytokines and chemokines. Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R-mediated nuclear factor kappaB activation, a reduction of LPS-, R848-, and IL-1-mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow-derived macrophages from IRAK4 kinase-inactive knock-in mice. Both TLR7- and TLR9-mediated type I interferon production was abolished in plasmacytoid dendritic cells isolated from IRAK4 knock-in mice. In addition, influenza virus-induced production of interferons in plasmacytoid DCs was also dependent on IRAK4 kinase activity. Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses.

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