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 κB (NF-κB). 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-κB 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.
MSU Digital Commons Citation
Kanakaraj, Palanisamy; Schafer, Peter H.; Cavender, Druie E.; Wu, Ying; Ngo, Karen; Grealish, Patrick F.; Wadsworth, Scott A.; Peterson, Per A.; Siekierka, John; Harris, Crafford A.; and Fung-Leung, Wai Ping, "Interleukin (IL)-1 Receptor-Associated Kinase (IRAK) Requirement for Optimal Induction of Multiple IL-1 Signaling Pathways and IL-6 Production" (1998). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 163.