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

Whan Kim Tae, Kirk Staschke, Katarzyna Bulek, Jianhong Yao, Kristi Peters, Keun Hee Oh, Yvonne Vandenburg, Hui Xiao, Wen Qian, Tom Hamilton, Booki Min, Ganes Sen, Raymond Gilmour*, Xiaoxia Li

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

202 Scopus citations

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 κB 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. JEM

Original languageEnglish (US)
Pages (from-to)1025-1036
Number of pages12
JournalJournal of Experimental Medicine
Volume204
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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