Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2.
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.
Kawagoe
Tatsukata
T
Laboratory of Host Defense, World Premier International Research Center, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Sato
Shintaro
S
Matsushita
Kazufumi
K
Kato
Hiroki
H
Matsui
Kosuke
K
Kumagai
Yutaro
Y
Saitoh
Tatsuya
T
Kawai
Taro
T
Takeuchi
Osamu
O
Akira
Shizuo
S
D000818:Animals; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051193:Toll-Like Receptors / Q000276:immunology*
D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases