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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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H. Xiong, C. Zhu, F. Li, R. Hegazi, K. He, M. Babyatsky, A. J. Bauer, and S. E. Plevy Inhibition of Interleukin-12 p40 Transcription and NF-{kappa}B Activation by Nitric Oxide in Murine Macrophages and Dendritic Cells J. Biol. Chem., March 12, 2004; 279(11): 10776 - 10783. [Abstract] [Full Text] [PDF]
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K. S. Kobayashi and R. A. Flavell Shielding the double-edged sword: negative regulation of the innate immune system J. Leukoc. Biol., March 1, 2004; 75(3): 428 - 433. [Abstract] [Full Text] [PDF]
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N. Suzuki, S. Suzuki, U. Eriksson, H. Hara, C. Mirtosis, N.-J. Chen, T. Wada, D. Bouchard, I. Hwang, K. Takeda, et al. IL-1R-Associated Kinase 4 Is Required for Lipopolysaccharide- Induced Activation of APC J. Immunol., December 1, 2003; 171(11): 6065 - 6071. [Abstract] [Full Text] [PDF]
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A. E. Medvedev, A. Lentschat, D. B. Kuhns, J. C.G. Blanco, C. Salkowski, S. Zhang, M. Arditi, J. I. Gallin, and S. N. Vogel Distinct Mutations in IRAK-4 Confer Hyporesponsiveness to Lipopolysaccharide and Interleukin-1 in a Patient with Recurrent Bacterial Infections J. Exp. Med., August 18, 2003; 198(4): 521 - 531. [Abstract] [Full Text] [PDF]
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C. Ropert, M. Closel, A. C. L. Chaves, and R. T. Gazzinelli Inhibition of a p38/Stress-Activated Protein Kinase-2-Dependent Phosphatase Restores Function of IL-1 Receptor-Associated Kinase-1 and Reverses Toll-Like Receptor 2- and 4-Dependent Tolerance of Macrophages J. Immunol., August 1, 2003; 171(3): 1456 - 1465. [Abstract] [Full Text] [PDF]
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J. A. Thomas, S. B. Haudek, T. Koroglu, M. F. Tsen, D. D. Bryant, D. J. White, D. F. Kusewitt, J. W. Horton, and B. P. Giroir IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction Am J Physiol Heart Circ Physiol, August 1, 2003; 285(2): H597 - H606. [Abstract] [Full Text] [PDF]
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 D. D. Bannerman and S. E. Goldblum Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L899 - L914. [Abstract] [Full Text] [PDF]
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S. E. Doyle, R. O'Connell, S. A. Vaidya, E. K. Chow, K. Yee, and G. Cheng Toll-Like Receptor 3 Mediates a More Potent Antiviral Response Than Toll-Like Receptor 4 J. Immunol., April 1, 2003; 170(7): 3565 - 3571. [Abstract] [Full Text] [PDF]
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C. Deng, C. Radu, A. Diab, M. F. Tsen, R. Hussain, J. S. Cowdery, M. K. Racke, and J. A. Thomas IL-1 Receptor-Associated Kinase 1 Regulates Susceptibility to Organ-Specific Autoimmunity J. Immunol., March 15, 2003; 170(6): 2833 - 2842. [Abstract] [Full Text] [PDF]
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A. Dunne and L. A. J. O'Neill The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense Sci. Signal., February 25, 2003; 2003(171): re3 - re3. [Abstract] [Full Text] [PDF]
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Liwu Li, R. Jacinto, B. Yoza, and C. E. McCall Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes Innate Immunity, February 1, 2003; 9(1): 39 - 44. [Abstract] [PDF]
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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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 C. Schmitt, A. Humeny, C.-M. Becker, K. Brune, and A. Pahl Polymorphisms of TLR4: Rapid Genotyping and Reduced Response to Lipopolysaccharide of TLR4 Mutant Alleles Clin. Chem., October 1, 2002; 48(10): 1661 - 1667. [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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 P.-L. Wang and K. Ohura PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE SIGNALING IN GINGIVAL FIBROBLASTS-CD14 AND TOLL-LIKE RECEPTORS Critical Reviews in Oral Biology & Medicine, March 1, 2002; 13(2): 132 - 142. [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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 N. Silverman and T. Maniatis NF-{kappa}B signaling pathways in mammalian and insect innate immunity Genes & Dev., September 15, 2001; 15(18): 2321 - 2342. [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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 M. A. Moors, L. Li, and S. B. Mizel Activation of Interleukin-1 Receptor-Associated Kinase by Gram-Negative Flagellin Infect. Immun., July 1, 2001; 69(7): 4424 - 4429. [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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T. Kaisho, O. Takeuchi, T. Kawai, K. Hoshino, and S. Akira Endotoxin-Induced Maturation of MyD88-Deficient Dendritic Cells J. Immunol., May 1, 2001; 166(9): 5688 - 5694. [Abstract] [Full Text] [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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S. B. Haudek, E. Spencer, D. D. Bryant, D. J. White, D. Maass, J. W. Horton, Z. J. Chen, and B. P. Giroir Overexpression of cardiac I-{kappa}B{alpha} prevents endotoxin-induced myocardial dysfunction Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H962 - H968. [Abstract] [Full Text] [PDF]
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A. Schmidt, E. Caron, and A. Hall Lipopolysaccharide-Induced Activation of {beta}2-Integrin Function in Macrophages Requires Irak Kinase Activity, p38 Mitogen- Activated Protein Kinase, and the Rap1 GTPase Mol. Cell. Biol., January 15, 2001; 21(2): 438 - 448. [Abstract] [Full Text]
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A. Visintin, A. Mazzoni, J. H. Spitzer, D. H. Wyllie, S. K. Dower, and D. M. Segal Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells J. Immunol., January 1, 2001; 166(1): 249 - 255. [Abstract] [Full Text] [PDF]
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Guolong Zhang and S. Ghosh Molecular mechanisms of NF-{kappa}B activation induced by bacterial lipopolysaccharide through Toll-like receptors Innate Immunity, December 1, 2000; 6(6): 453 - 457. [Abstract] [PDF]
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G. Zhang and S. Ghosh Negative Regulation of Toll-like Receptor-mediated Signaling by Tollip J. Biol. Chem., February 22, 2002; 277(9): 7059 - 7065. [Abstract] [Full Text] [PDF]
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