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,
Departments of
*
Pharmacology,
Pediatrics, and
Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235
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-
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.
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K. Burns, S. Janssens, B. Brissoni, N. Olivos, R. Beyaert, and J. Tschopp Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4 J. Exp. Med., January 20, 2003; 197(2): 263 - 268. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, J.-G. Yoon, S.-C. Hong, and A.-K. Yi CpG DNA Induces Self and Cross-Hyporesponsiveness of RAW264.7 Cells in Response to CpG DNA and Lipopolysaccharide: Alterations in IL-1 Receptor-Associated Kinase Expression J. Immunol., January 15, 2003; 170(2): 1052 - 1061. [Abstract] [Full Text] [PDF]
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S. Bozinovski, J. E. Jones, R. Vlahos, J. A. Hamilton, and G. P. Anderson Granulocyte/Macrophage-Colony-stimulating Factor (GM-CSF) Regulates Lung Innate Immunity to Lipopolysaccharide through Akt/Erk Activation of NFkappa B and AP-1 in Vivo J. Biol. Chem., November 1, 2002; 277(45): 42808 - 42814. [Abstract] [Full Text] [PDF]
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D. Haller, M. P. Russo, R. B. Sartor, and C. Jobin IKKbeta and Phosphatidylinositol 3-Kinase/Akt Participate in Non-pathogenic Gram-negative Enteric Bacteria-induced RelA Phosphorylation and NF-kappa B Activation in Both Primary and Intestinal Epithelial Cell Lines J. Biol. Chem., October 4, 2002; 277(41): 38168 - 38178. [Abstract] [Full Text] [PDF]
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B. Billack, D. E. Heck, T. M. Mariano, C. R. Gardner, R. Sur, D. L. Laskin, and J. D. Laskin Induction of cyclooxygenase-2 by heat shock protein 60 in macrophages and endothelial cells Am J Physiol Cell Physiol, October 1, 2002; 283(4): C1267 - C1277. [Abstract] [Full Text] [PDF]
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J. A. Thomas, M. F. Tsen, D. J. White, and J. W. Horton IRAK contributes to burn-triggered myocardial contractile dysfunction Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H829 - H836. [Abstract] [Full Text] [PDF]
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 M.M. Monick and G.W. Hunninghake Activation of second messenger pathways in alveolar macrophages by endotoxin Eur. Respir. J., July 1, 2002; 20(1): 210 - 222. [Abstract] [Full Text] [PDF]
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J. Radons, S. Gabler, H. Wesche, C. Korherr, R. Hofmeister, and W. Falk Identification of Essential Regions in the Cytoplasmic Tail of Interleukin-1 Receptor Accessory Protein Critical for Interleukin-1 Signaling J. Biol. Chem., May 3, 2002; 277(19): 16456 - 16463. [Abstract] [Full Text] [PDF]
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J. Hu, R. Jacinto, C. McCall, and L. Li Regulation of IL-1 Receptor-Associated Kinases by Lipopolysaccharide J. Immunol., April 15, 2002; 168(8): 3910 - 3914. [Abstract] [Full Text] [PDF]
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D. D. Bannerman, J. C. Tupper, R. D. Erwert, R. K. Winn, and J. M. Harlan Divergence of Bacterial Lipopolysaccharide Pro-apoptotic Signaling Downstream of IRAK-1 J. Biol. Chem., March 1, 2002; 277(10): 8048 - 8053. [Abstract] [Full Text] [PDF]
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G. Wright, I. S. Singh, J. D. Hasday, I. K. Farrance, G. Hall, A. S. Cross, and T. B. Rogers Endotoxin stress-response in cardiomyocytes: NF-kappa B activation and tumor necrosis factor-alpha expression Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H872 - H879. [Abstract] [Full Text] [PDF]
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A. E. Medvedev, P. Henneke, A. Schromm, E. Lien, R. Ingalls, M. J. Fenton, D. T. Golenbock, and S. N. Vogel Induction of Tolerance to Lipopolysaccharide and Mycobacterial Components in Chinese Hamster Ovary/CD14 Cells Is Not Affected by Overexpression of Toll-Like Receptors 2 or 4 J. Immunol., August 15, 2001; 167(4): 2257 - 2267. [Abstract] [Full Text] [PDF]
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C. Alexander and E. Th. Rietschel Invited review: Bacterial lipopolysaccharides and innate immunity Innate Immunity, June 1, 2001; 7(3): 167 - 202. [Abstract] [PDF]
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M. M. Monick, A. B. Carter, P. K. Robeff, D. M. Flaherty, M. W. Peterson, and G. W. Hunninghake Lipopolysaccharide Activates Akt in Human Alveolar Macrophages Resulting in Nuclear Accumulation and Transcriptional Activity of {{beta}}-Catenin J. Immunol., April 1, 2001; 166(7): 4713 - 4720. [Abstract] [Full Text] [PDF]
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