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 Siekierka, Crafford A. Harris, Wai Ping Fung-Leung

Research output: Contribution to journalArticle

169 Citations (Scopus)

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

Fingerprint

Interleukin-1 Receptor-Associated Kinases
Interleukin-1
Interleukin-6
Fibroblasts
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Keywords

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

Cite this

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. ; 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. In: Journal of Experimental Medicine. 1998 ; Vol. 187, No. 12. pp. 2073-2079.
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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.",
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author = "Palanisamy Kanakaraj and Schafer, {Peter H.} and Cavender, {Druie E.} and Ying Wu and Karen Ngo and Grealish, {Patrick F.} and Wadsworth, {Scott A.} and Peterson, {Per A.} and John Siekierka and Harris, {Crafford A.} and Fung-Leung, {Wai Ping}",
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Kanakaraj, P, Schafer, PH, Cavender, DE, Wu, Y, Ngo, K, Grealish, PF, Wadsworth, SA, Peterson, PA, Siekierka, J, Harris, CA & Fung-Leung, WP 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, vol. 187, no. 12, pp. 2073-2079. https://doi.org/10.1084/jem.187.12.2073

Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production. / 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.; Fung-Leung, Wai Ping.

In: Journal of Experimental Medicine, Vol. 187, No. 12, 15.06.1998, p. 2073-2079.

Research output: Contribution to journalArticle

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T1 - Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production

AU - Kanakaraj, Palanisamy

AU - Schafer, Peter H.

AU - Cavender, Druie E.

AU - Wu, Ying

AU - Ngo, Karen

AU - Grealish, Patrick F.

AU - Wadsworth, Scott A.

AU - Peterson, Per A.

AU - Siekierka, John

AU - Harris, Crafford A.

AU - Fung-Leung, Wai Ping

PY - 1998/6/15

Y1 - 1998/6/15

N2 - 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.

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