Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling.
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 kappaB (NF-kappaB). 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-kappaB-regulated genes in response to TLR ligands such as tumor necrosis factor alpha and IkappaBzeta. 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.
Kawagoe
Tatsukata
T
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Sato
Shintaro
S
Jung
Andreas
A
Yamamoto
Masahiro
M
Matsui
Kosuke
K
Kato
Hiroki
H
Uematsu
Satoshi
S
Takeuchi
Osamu
O
Akira
Shizuo
S
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D024202:Electrophoretic Mobility Shift Assay; D007113:Immunity, Innate / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
D016207:Cytokines; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases