The Journal of Experimental Medicine
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Published online 14 March 2005 doi:10.1084/jem.20042372
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 6, 915-923
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ARTICLE

 Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction

Satoshi Uematsu1, Shintaro Sato3, Masahiro Yamamoto1, Tomonori Hirotani1, Hiroki Kato1, Fumihiko Takeshita4, Michiyuki Matsuda2, Cevayir Coban5, Ken J. Ishii3, Taro Kawai3, Osamu Takeuchi1,3, and Shizuo Akira1,3

1 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita Osaka 565-0871, Japan
2 Department of Tumor Biology, Research Institute for Microbial Diseases, Osaka University, Suita Osaka 565-0871, Japan
3 ERATO, Japan Science and Technology Agency, Suita Osaka 565-0871, Japan
4 Department of Molecular Biodefense Research, Yokohama City University School of Medicine, Kanazawaku, Yokohama 236-0004, Japan
5 21st Century COE, Combined Program on Microbiology and Immunology, Osaka University, Suita Osaka 565-0871, Japan

CORRESPONDENCE Shizuo Akira: sakira{at}biken.osaka-u.ac.jp

Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-{alpha} in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-{alpha} production was abolished in Irak-1–deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-{kappa}B and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1–deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-{alpha} induction in pDCs.

Abbreviations used: CFP, cyan fluorescent protein; CpG ODN, CpG oligodeoxynucleotides; ds, double stranded; EF, embryonic fibroblast; ELAM, endothelial leukocyte adhesion molecule; Flt3L, Flt3 ligand; FRET, fluorescence resonance energy transfer; HEK, human embryonic kidney; IKKi, inducible IKK; IRAK, IL-1 receptor-associated kinase; JNK, c-Jun NH2-terminal kinase; KN, kinase negative; MAPK, mitogen-activated protein kinases; MKK4, MAPK kinase 4; ss, single stranded; TBK1, TANK-binding kinase 1; TIR, Toll–IL-1 receptor; TLR, Toll-like receptor; TRAF, TNF receptor-associated factor; YFP, yellow fluorescent protein.


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