Irak requirement for optimal induction by IL-I of multiple signaling pathways

IL 1 is a proinflammatory cytokine with pleiotropic effects in systemic and local inflammatory responses. IL 1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated MAP kinases, c-Jun N-terminal kinase (JNK) and p38, as well as transcription factors such as NFkB. Upon IL-1 binding, IL-1 receptor type 1 forms a complex with IL-1 receptor accessory protein (IL-1R AcP). IL-1 receptor associated kinase (IRAK) rapidly interacts with this receptor complex, becomes phosphorylated and subsequently interacts with other signaling molecules such as TNF receptor associated factor (TRAF6). IRAK is related to Pelle, a Drosophila protein kinase essential for activation of Dorsal, an NF-kB like protein mediated by Toll which is an IL 1 receptor homologue in Drosophila. The association of IRAK with the IL 1 receptor complex, along with its homology to Pelle, suggests that IRAK could play an important role in IL-1 signaling. We generated embryonic fibroblast cells deficient in IRAK to study the role of IRAK in IL-1 mediated signaling and cellular response. The IRAK deficient cells exhibit IL-1 signaling deficiencies which clearly implicate IRAK as an important component of the IL-1 receptor signaling cascade.