Article abstract
Nature Immunology 9, 684 - 691 (2008)
Published online: 27 April 2008 | doi:10.1038/ni.1606
Sequential control of Toll-like receptor–dependent responses by IRAK1 and IRAK2
Tatsukata Kawagoe1,2, Shintaro Sato3, Kazufumi Matsushita1,2, Hiroki Kato1,2, Kosuke Matsui2, Yutaro Kumagai1,2, Tatsuya Saitoh1,2, Taro Kawai1,2,3, Osamu Takeuchi1,2,3 & Shizuo Akira1,2,3
Abstract
Members of the IRAK family of kinases mediate Toll-like receptor (TLR) signaling. Here we show that IRAK2 was essential for sustaining TLR-induced expression of genes encoding cytokines and activation of the transcription factor NF-
B, despite the fact that IRAK2 was dispensable for activation of the initial signaling cascades. IRAK2 was activated 'downstream' of IRAK4, like IRAK1, and TLR-induced cytokine production was abrogated in the absence of both IRAK1 and IRAK2. Whereas the kinase activity of IRAK1 decreased within 1 h of TLR2 stimulation, coincident with IRAK1 degradation, the kinase activity of IRAK2 was sustained and peaked at 8 h after stimulation. Thus, IRAK2 is critical in late-phase TLR responses, and IRAK1 and IRAK2 are essential for the initial responses to TLR stimulation.
- Laboratory of Host Defense, World Premier International Research Center, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
- Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
- Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Correspondence to: Shizuo Akira1,2,3 e-mail: sakira@biken.osaka-u.ac.jp
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