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-κB, 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.
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Acknowledgements
We thank J.A. Thomas (University of Texas Southern Medical Center) for Irak1–/– mice; all our colleagues in our laboratory; M. Hashimoto for secretarial assistance; and Y. Fujiwara, M. Shiokawa, A. Shibano and N. Kitagaki for technical assistance. Supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Ministry of Health, Labour and Welfare of Japan; the 21st Century Center of Excellence Program of Japan; and the National Institutes of Health (AI070167).
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T. Kawagoe, O.T. and S.A. designed the research and analyzed data; T. Kawagoe did most of the experiments; S.S., K. Matsushita., H.K., K. Matsui., Y.K., T.S. and T.K. provided advice; and T. Kawagoe, O.T. and S.A. prepared the manuscript.
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Supplementary Table 1
Gene lists and expression profiles of MALP-2-inducible genes in wild-type, Irak2–/– and Irak1–/YIrak2–/– macrophages (XLS 79 kb)
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Kawagoe, T., Sato, S., Matsushita, K. et al. Sequential control of Toll-like receptor–dependent responses by IRAK1 and IRAK2. Nat Immunol 9, 684–691 (2008). https://doi.org/10.1038/ni.1606
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DOI: https://doi.org/10.1038/ni.1606
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