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Nat Immunol. 2008 Jun;9(6):684-91. doi: 10.1038/ni.1606. Epub 2008 Apr 27.

Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2.

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Laboratory of Host Defense, World Premier International Research Center, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.


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-kappaB, 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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