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¹ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
² Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Suita, Osaka 565-0871, Japan

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

Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor B (NF-B). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4^KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4^KN/KN as well as IRAK-4^–/– macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-B–regulated genes in response to TLR ligands such as tumor necrosis factor and IB. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4^–/– and IRAK-4^KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.

Abbreviations used: Ab, antibody; COX-2, cyclooxygenase-2; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal-regulated kinase; ES, embryonic stem; IKK-, IB kinase ; IL-1R, IL-1 receptor; IRAK, IL-1R–associated kinase; JNK, c-Jun N-terminal kinase; LCMV, lymphocytic choriomeningitis virus; MALP-2, macrophage-activating lipopeptide-2; MAP, mitogen-activated protein; MEF, mouse embryonic fibroblast; mRNA, messenger RNA; pDC, plasmacytoid DC; TIR, Toll/IL-1R; TLR, Toll-like receptor; TRAF6, TNF receptor–associated factor 6.

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