Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production

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, Wai Ping Fung-Leung

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170 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2073-2079
Number of pages7
JournalJournal of Experimental Medicine
Volume187
Issue number12
DOIs
StatePublished - Jun 15 1998

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Keywords

  • IL-1
  • IRAK
  • JNK
  • NF-κB
  • p38

Cite this

Kanakaraj, P., Schafer, P. H., Cavender, D. E., Wu, Y., Ngo, K., Grealish, P. F., Wadsworth, S. A., Peterson, P. A., Siekierka, J. J., Harris, C. A., & Fung-Leung, W. P. (1998). Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production. Journal of Experimental Medicine, 187(12), 2073-2079. https://doi.org/10.1084/jem.187.12.2073