J. Exp. Med., Volume 187, Number 12, June 15, 1998 2073-2079

Interleukin (IL)-1 Receptor-associated Kinase (IRAK) Requirement for Optimal Induction of Multiple IL-1 Signaling Pathways and IL-6 Production

By Palanisamy Kanakaraj,^* Peter H. Schafer, Druie E. Cavender, Ying Wu,^* Karen Ngo,^* Patrick F. Grealish, Scott A. Wadsworth, Per A. Peterson, John J. Siekierka, Crafford A. Harris, and Wai-Ping Fung-Leung^*

From the ^* R.W. Johnson Pharmaceutical Research Institute, San Diego, California 92121; and the  R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869

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 B (NF-B). 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-B 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.

IRAK;  IL-1;  JNK;  p38;  NF-B

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• Vig, E., Green, M., Liu, Y., Donner, D. B., Mukaida, N., Goebl, M. G., Harrington, M. A. (1999). Modulation of Tumor Necrosis Factor and Interleukin-1-dependent NF-kappa B Activity by mPLK/IRAK. J. Biol. Chem. 274: 13077-13084 [Abstract] [Full Text]  
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• Bonizzi, G., Piette, J., Schoonbroodt, S., Greimers, R., Havard, L., Merville, M.-P., Bours, V. (1999). Reactive Oxygen Intermediate-Dependent NF-kappa B Activation by Interleukin-1beta Requires 5-Lipoxygenase or NADPH Oxidase Activity. Mol. Cell. Biol. 19: 1950-1960 [Abstract] [Full Text]  
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• MacGillivray, M. K., Cruz, T. F., McCulloch, C. A. G. (2000). The Recruitment of the Interleukin-1 (IL-1) Receptor-associated Kinase (IRAK) into Focal Adhesion Complexes Is Required for IL-1beta -induced ERK Activation. J. Biol. Chem. 275: 23509-23515 [Abstract] [Full Text]  
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