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 effe cts in inflammation. IL-1 binding to its receptor triggers a cascade o f signaling events, including activation of the stress-activated mitog en-activated protein (MAP) kinases, c-Jun NH2-terminal kinase (JNK) an d p38 MAP kinase, as well as transcription factor nuclear factor kappa B (NF-kappa B). IL-1 signaling results in cellular responses through induction of inflammatory gene products such as IL-6. One of the earli est events in IL-1 signaling is the rapid interaction of IL-1 receptor -associated kinases, IRAK and IRAK-2, with the receptor complex. The r elative roles of IRAK and IRAK-2 in IL-1 signaling pathways and subseq uent cellular responses have not been previously determined. To evalua te the importance of IRAK in IL-1 signaling, IRAK-deficient mouse fibr oblast cells were prepared and studied. Here we report that IL-1-media ted activation of JNK, p38, and NF-kappa B were all reduced in embryon ic fibroblasts deficient in IRAK expression. In addition, IL-6 product ion in response to IL-1 was also dramatically reduced in IRAK-deficien t embryonic fibroblasts and in skin fibroblasts prepared from IRAK-def icient mice. Our results demonstrate that IRAK plays an essential prox imal role in coordinating multiple IL-1signaling pathways for optimal induction of cellular responses.