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* Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201;
National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; and
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605
Prior exposure to LPS induces a transient state of cell
refractoriness to subsequent LPS restimulation, known as endotoxin
tolerance. Induction of LPS tolerance has been reported to correlate
with decreased cell surface expression of the LPS receptor complex,
Toll-like receptor 4 (TLR4)/MD-2. However, other results have
underscored the existence of mechanisms of LPS tolerance that operate
downstream of TLR4/MD-2. In the present study we sought to delineate
further the molecular basis of LPS tolerance by examining the TLR4
signaling pathway in endotoxin-tolerant cells. Pretreatment of human
monocytes with LPS decreased LPS-mediated NF-
B activation, p38
mitogen-activated protein kinase phosphorylation, and TNF-
gene
expression, documenting the induction of endotoxin tolerance. FACS and
Western blot analyses of LPS-tolerant monocytes showed increased TLR2
expression, whereas TLR4 expression levels were not affected.
Comparable levels of mRNA and protein for myeloid differentiation
factor 88 (MyD88), IL-1R-associated kinase 1 (IRAK-1), and
TNFR-associated factor-6 were found in normal and LPS-tolerant
monocytes, while MD-2 mRNA expression was slightly increased in
LPS-tolerant cells. LPS induced the association of MyD88 with TLR4 and
increased IRAK-1 activity in medium-pretreated cells. In LPS-tolerant
monocytes, however, MyD88 failed to be recruited to TLR4, and IRAK-1
was not activated in response to LPS stimulation. Moreover,
endotoxin-tolerant CHO cells that overexpress human TLR4 and MD-2 also
showed decreased IRAK-1 kinase activity in response to LPS despite the
failure of LPS to inhibit cell surface expression of transfected TLR4
and MD-2 proteins. Thus, decreased TLR4-MyD88 complex formation with
subsequent impairment of IRAK-1 activity may underlie the LPS-tolerant
phenotype.
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M. Siedlar, M. Frankenberger, E. Benkhart, T. Espevik, M. Quirling, K. Brand, M. Zembala, and L. Ziegler-Heitbrock Tolerance Induced by the Lipopeptide Pam3Cys Is Due to Ablation of IL-1R-Associated Kinase-1 J. Immunol., August 15, 2004; 173(4): 2736 - 2745. [Abstract] [Full Text] [PDF]
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 J. Roman, J. D. Ritzenthaler, B. Boles, M. Lois, and S. Roser-Page Lipopolysaccharide induces expression of fibronectin {alpha}5{beta}1-integrin receptors in human monocytic cells in a protein kinase C-dependent fashion Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L239 - L249. [Abstract] [Full Text] [PDF]
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S. Noubir, Z. Hmama, and N. E. Reiner Dual Receptors and Distinct Pathways Mediate Interleukin-1 Receptor-associated Kinase Degradation in Response to Lipopolysaccharide: INVOLVEMENT OF CD14/TLR4, CR3, AND PHOSPHATIDYLINOSITOL 3-KINASE J. Biol. Chem., June 11, 2004; 279(24): 25189 - 25195. [Abstract] [Full Text] [PDF]
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S. L. McCoy, S. E. Kurtz, F. A. Hausman, D. R. Trune, R. M. Bennett, and S. H. Hefeneider Activation of RAW264.7 Macrophages by Bacterial DNA and Lipopolysaccharide Increases Cell Surface DNA Binding and Internalization J. Biol. Chem., April 23, 2004; 279(17): 17217 - 17223. [Abstract] [Full Text] [PDF]
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L. C. Parker, M. K. B. Whyte, S. N. Vogel, S. K. Dower, and I. Sabroe Toll-Like Receptor (TLR)2 and TLR4 Agonists Regulate CCR Expression in Human Monocytic Cells J. Immunol., April 15, 2004; 172(8): 4977 - 4986. [Abstract] [Full Text] [PDF]
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Hongkuan Fan and J. A. Cook Review: Molecular mechanisms of endotoxin tolerance Innate Immunity, April 1, 2004; 10(2): 71 - 84. [Abstract] [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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K. Nakayama, S. Okugawa, S. Yanagimoto, T. Kitazawa, K. Tsukada, M. Kawada, S. Kimura, K. Hirai, Y. Takagaki, and Y. Ota Involvement of IRAK-M in Peptidoglycan-induced Tolerance in Macrophages J. Biol. Chem., February 20, 2004; 279(8): 6629 - 6634. [Abstract] [Full Text] [PDF]
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G. Hajishengallis and R. J. Genco Downregulation of the DNA-Binding Activity of Nuclear Factor-{kappa}B p65 Subunit in Porphyromonas gingivalis Fimbria-Induced Tolerance Infect. Immun., February 1, 2004; 72(2): 1188 - 1191. [Abstract] [Full Text] [PDF]
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B. Mytar, M. Woloszyn, R. Szatanek, M. Baj-Krzyworzeka, M. Siedlar, I. Ruggiero, J. Wieckiewicz, and M. Zembala Tumor cell-induced deactivation of human monocytes J. Leukoc. Biol., December 1, 2003; 74(6): 1094 - 1101. [Abstract] [Full Text]
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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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I. Sabroe, R. C. Read, M. K. B. Whyte, D. H. Dockrell, S. N. Vogel, and S. K. Dower Toll-Like Receptors in Health and Disease: Complex Questions Remain J. Immunol., August 15, 2003; 171(4): 1630 - 1635. [Full Text] [PDF]
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U. Deiters, M. Gumenscheimer, C. Galanos, and P. F. Muhlradt Toll-Like Receptor 2- and 6-Mediated Stimulation by Macrophage-Activating Lipopeptide 2 Induces Lipopolysaccharide (LPS) Cross Tolerance in Mice, Which Results in Protection from Tumor Necrosis Factor Alpha but in Only Partial Protection from Lethal LPS Doses Infect. Immun., August 1, 2003; 71(8): 4456 - 4462. [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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T. Bartfai, M. M. Behrens, S. Gaidarova, J. Pemberton, A. Shivanyuk, and J. Rebek Jr A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses PNAS, June 24, 2003; 100(13): 7971 - 7976. [Abstract] [Full Text] [PDF]
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A. E. Medvedev and S. N. Vogel Overexpression of CD14, TLR4, and MD-2 in HEK 293T cells does not prevent induction of in vitro endotoxin tolerance Innate Immunity, February 1, 2003; 9(1): 60 - 64. [Abstract] [PDF]
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M. A. Dobrovolskaia, A. E. Medvedev, K. E. Thomas, N. Cuesta, V. Toshchakov, T. Ren, M. J. Cody, S. M. Michalek, N. R. Rice, and S. N. Vogel Induction of In Vitro Reprogramming by Toll-Like Receptor (TLR)2 and TLR4 Agonists in Murine Macrophages: Effects of TLR "Homotolerance" Versus "Heterotolerance" on NF-{kappa}B Signaling Pathway Components J. Immunol., January 1, 2003; 170(1): 508 - 519. [Abstract] [Full Text] [PDF]
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