DOI: 10.4049/jimmunol.164.8.4301. IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin

IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin

10.4049/jimmunol.164.8.4301

Crossref journal-article

Oxford University Press (OUP)

The Journal of Immunology (286)

Abstract

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.

Bibliography

Swantek, J. L., Tsen, M. F., Cobb, M. H., & Thomas, J. A. (2000). IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin. The Journal of Immunology, 164(8), 4301â4306.

Authors 4

Jennifer L Swantek (first)
May F Tsen (additional)
Melanie H Cobb (additional)
James A Thomas (additional)

References 41 Referenced 222

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Dates

Type	When
Created	11 years, 4 months ago (April 21, 2014, 10:13 p.m.)
Deposited	4 months, 3 weeks ago (March 31, 2025, 8:01 a.m.)
Indexed	4 months, 3 weeks ago (March 31, 2025, 8:40 a.m.)
Issued	25 years, 4 months ago (April 1, 2000)
Published	25 years, 4 months ago (April 1, 2000)
Published Online	25 years, 4 months ago (April 15, 2000)
Published Print	25 years, 4 months ago (April 15, 2000)

Funders 0

None

BibTeX

@article{Swantek_2000, title={IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin}, volume={164}, ISSN={1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.164.8.4301}, DOI={10.4049/jimmunol.164.8.4301}, number={8}, journal={The Journal of Immunology}, publisher={Oxford University Press (OUP)}, author={Swantek, Jennifer L and Tsen, May F and Cobb, Melanie H and Thomas, James A}, year={2000}, month=apr, pages={4301–4306} }

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  "abstract": "<jats:title>Abstract</jats:title>\n               <jats:p>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-\u03b1 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.</jats:p>",
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