The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online April 30, 2007
doi:10.1084/jem.20061825
The Journal of Experimental Medicine, Vol. 204, No. 5, 1025-1036
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Kim et al.
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ARTICLE

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

Tae Whan Kim1,4, Kirk Staschke3, Katarzyna Bulek1, Jianhong Yao1, Kristi Peters2, Keun-Hee Oh1, Yvonne Vandenburg3, Hui Xiao1, Wen Qian1, Tom Hamilton1, Booki Min1, Ganes Sen2, Raymond Gilmour3, and Xiaoxia Li1

1 Department of Immunology, 2 Department of Molecular Genetics, Cleveland Clinic Foundation, 3 Lilly Research Laboratories, Indianapolis, 46285 IN
4 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106

CORRESPONDENCE R. Gilmour: gilmour_raymond{at}lilly.com OR X. Li:lix{at}ccf.org

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 {kappa}B 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.

Abbreviations used: IKK, I{kappa}B kinase; IRAK, IL-1 receptor–associated kinase; IRF, interferon regulatory factor; JNK, c-Jun NH2-terminal kinase; KC, chemokine; mDC, myeloid DC; MEF, mouse embryonic fibroblast; ODN, oligodeoxynucleotide; pDC, plasmacytoid DC; TAK1, TGF-ß–activated kinase 1; TLR, Toll-like receptor.

T.W. Kim and K. Staschke contributed equally to this work.


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