IL-1 receptor-associated kinase modulates host responsiveness to endotoxin

Jennifer L. Swantek, May F. Tsen, Melanie H. Cobb, James A. Thomas

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218 Scopus citations

Abstract

Endotoxin triggers many of the inflammatory, hemodynamic, and hematological derangements of Gram-negative septic shock. Recent genetic studies in mice have identified the Toll-like receptor 4 as the transmembrane endotoxin signal transducer. The IL-1 intracellular signaling pathway has been implicated in Toll-like receptor signal transduction. LPS-induced activation of the IL-1 receptor-associated kinase (IRAK), and the influence of IRAK on intracellular signaling and cellular responses to endotoxin has not been explored in relevant innate immune cells. We demonstrate that LPS activates IRAK in murine macrophages. IRAK-deficient macrophages, in contrast, are resistant to LPS. Deletion of IRAK disrupts several endotoxin- triggered signaling cascades. Furthermore, macrophages lacking IRAK exhibit impaired LPS-stimulated TNF-α production, and IRAK-deficient mice withstand the lethal effects of LPS. These findings, coupled with the critical role for IRAK in IL-1 and IL-18 signal transduction, demonstrate the importance of this kinase and the IL-1/Toll signaling cassette in sensing and responding to Gram-negative infection.

Original languageEnglish (US)
Pages (from-to)4301-4306
Number of pages6
JournalJournal of Immunology
Volume164
Issue number8
Publication statusPublished - Apr 15 2000

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ASJC Scopus subject areas

  • Immunology

Cite this

Swantek, J. L., Tsen, M. F., Cobb, M. H., & Thomas, J. A. (2000). IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. Journal of Immunology, 164(8), 4301-4306.