Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production.
Interleukin (IL)-1 is a proinflammatory cytokine with pleiotropic effects in inflammation. IL-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (MAP) kinases, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, as well as transcription factor nuclear factor kappaB (NF-kappaB). IL-1 signaling results in cellular responses through induction of inflammatory gene products such as IL-6. One of the earliest events in IL-1 signaling is the rapid interaction of IL-1 receptor-associated kinases, IRAK and IRAK-2, with the receptor complex. The relative roles of IRAK and IRAK-2 in IL-1 signaling pathways and subsequent cellular responses have not been previously determined. To evaluate the importance of IRAK in IL-1 signaling, IRAK-deficient mouse fibroblast cells were prepared and studied. Here we report that IL-1-mediated activation of JNK, p38, and NF-kappaB were all reduced in embryonic fibroblasts deficient in IRAK expression. In addition, IL-6 production in response to IL-1 was also dramatically reduced in IRAK-deficient embryonic fibroblasts and in skin fibroblasts prepared from IRAK-deficient mice. Our results demonstrate that IRAK plays an essential proximal role in coordinating multiple IL-1 signaling pathways for optimal induction of cellular responses.
Kanakaraj
P
P
R.W. Johnson Pharmaceutical Research Institute, San Diego, California 92121, USA.
Schafer
P H
PH
Cavender
D E
DE
Wu
Y
Y
Ngo
K
K
Grealish
P F
PF
Wadsworth
S A
SA
Peterson
P A
PA
Siekierka
J J
JJ
Harris
C A
CA
Fung-Leung
W P
WP
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D007375:Interleukin-1 / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases; D015850:Interleukin-6 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology; D014960:X Chromosome; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases