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Departments of
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Internal Medicine and
Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75235;
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121;
§
Medical Intensive Care Unit, University of Geneva, Geneva, Switzerland;
¶
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; and
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Department of Molecular Medicine, North Shore University Hospital/Cornell University Medical College, Manhasset, NY 11030
Lipoproteins of Treponema pallidum and Borrelia burgdorferi possess potent proinflammatory properties and, thus, have been implicated as major proinflammatory agonists in syphilis and Lyme disease. Here we used purified B. burgdorferi outer surface protein A (OspA) and synthetic lipopeptides corresponding to the N-termini of OspA and the 47-kDa major lipoprotein immunogen of T. pallidum to clarify the contribution of CD14 to monocytic cell activation by spirochetal lipoproteins and lipopeptides. As with LPS, mouse anti-human CD14 Abs blocked the activation of 1,25-dihydroxyvitamin D3-matured human myelomonocytic THP-1 cells by OspA and the two lipopeptides. The existence of a CD14-dependent pathway was corroborated by using undifferentiated THP-1 cells transfected with CD14 and peritoneal macrophages from CD14-deficient BALB/c mice. Unlike LPS, cell activation by lipoproteins and lipopeptides was serum independent and was not augmented by exogenous LPS-binding protein. Two observations constituted evidence that LPS and lipoprotein/lipopeptide signaling proceed via distinct transducing elements downstream of CD14: 1) CHO cells transfected with CD14 were exquisitely sensitive to LPS but were lipoprotein/lipopeptide nonresponsive; and 2) substoichiometric amounts of deacylated LPS that block LPS signaling at a site distal to CD14 failed to antagonize activation by lipoproteins and lipopeptides. The combined results demonstrate that spirochetal lipoproteins and lipopeptides use a CD14-dependent pathway that differs in at least two fundamental respects from the well-characterized LPS recognition pathway.
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R. R. Ingalls, E. Lien, and D. T. Golenbock Membrane-Associated Proteins of a Lipopolysaccharide-Deficient Mutant of Neisseria meningitidis Activate the Inflammatory Response through Toll-Like Receptor 2 Infect. Immun., April 1, 2001; 69(4): 2230 - 2236. [Abstract] [Full Text] [PDF]
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S. D. C. Pfannes, B. Müller, S. Körner, W. G. Bessler, and P. Hoffmann Induction of soluble antitumoral mediators by synthetic analogues of bacterial lipoprotein in bone marrow-derived macrophages from LPS-responder and -nonresponder mice J. Leukoc. Biol., April 1, 2001; 69(4): 590 - 597. [Abstract] [Full Text]
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T. J. Sellati, S. L. Waldrop, J. C. Salazar, P. R. Bergstresser, L. J. Picker, and J. D. Radolf The Cutaneous Response in Humans to Treponema pallidum Lipoprotein Analogues Involves Cellular Elements of Both Innate and Adaptive Immunity J. Immunol., March 15, 2001; 166(6): 4131 - 4140. [Abstract] [Full Text] [PDF]
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J. A. Gebbia, J. L. Coleman, and J. L Benach Borrelia Spirochetes Upregulate Release and Activation of Matrix Metalloproteinase Gelatinase B (MMP-9) and Collagenase 1 (MMP-1) in Human Cells Infect. Immun., January 1, 2001; 69(1): 456 - 462. [Abstract] [Full Text] [PDF]
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D. A. Bouis, T. G. Popova, A. Takashima, and M. V. Norgard Dendritic Cells Phagocytose and Are Activated by Treponema pallidum Infect. Immun., January 1, 2001; 69(1): 518 - 528. [Abstract] [Full Text] [PDF]
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P. K. Murthy, V. A. Dennis, B. L. Lasater, and M. T. Philipp Interleukin-10 Modulates Proinflammatory Cytokines in the Human Monocytic Cell Line THP-1 Stimulated with Borrelia burgdorferi Lipoproteins Infect. Immun., December 1, 2000; 68(12): 6663 - 6669. [Abstract] [Full Text] [PDF]
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R. R. Ingalls, E. Lien, and D. T. Golenbock Differential roles of TLR2 and TLR4 in the host response to Gram-negative bacteria: lessons from a lipopolysaccharide-deficient mutant of Neisseria meningitidis Innate Immunity, October 1, 2000; 6(5): 411 - 415. [Abstract] [PDF]
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N. W. J. Schroder, B. Opitz, N. Lamping, K. S. Michelsen, U. Zahringer, U. B. Gobel, and R. R. Schumann Involvement of Lipopolysaccharide Binding Protein, CD14, and Toll-Like Receptors in the Initiation of Innate Immune Responses by Treponema Glycolipids J. Immunol., September 1, 2000; 165(5): 2683 - 2693. [Abstract] [Full Text] [PDF]
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E. Lien, T. J. Sellati, A. Yoshimura, T. H. Flo, G. Rawadi, R. W. Finberg, J. D. Carroll, T. Espevik, R. R. Ingalls, J. D. Radolf, et al. Toll-like Receptor 2 Functions as a Pattern Recognition Receptor for Diverse Bacterial Products J. Biol. Chem., November 19, 1999; 274(47): 33419 - 33425. [Abstract] [Full Text] [PDF]
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J. P. Brown, J. F. Zachary, C. Teuscher, J. J. Weis, and R. M. Wooten Dual Role of Interleukin-10 in Murine Lyme Disease: Regulation of Arthritis Severity and Host Defense Infect. Immun., October 1, 1999; 67(10): 5142 - 5150. [Abstract] [Full Text] [PDF]
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M. Hirschfeld, C. J. Kirschning, R. Schwandner, H. Wesche, J. H. Weis, R. M. Wooten, and J. J. Weis Cutting Edge: Inflammatory Signaling by Borrelia burgdorferi Lipoproteins Is Mediated by Toll-Like Receptor 2 J. Immunol., September 1, 1999; 163(5): 2382 - 2386. [Abstract] [Full Text] [PDF]
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T. J. Sellati, D. A. Bouis, M. J. Caimano, J. A. Feulner, C. Ayers, E. Lien, and J. D. Radolf Activation of Human Monocytic Cells by Borrelia burgdorferi and Treponema pallidum Is Facilitated by CD14 and Correlates with Surface Exposure of Spirochetal Lipoproteins J. Immunol., August 15, 1999; 163(4): 2049 - 2056. [Abstract] [Full Text] [PDF]
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 A. O. Aliprantis, R. Yang, M. R. Mark, S. Suggett, B. Devaux, J. D. Radolf, G. R. Klimpel, P. Godowski, and A. Zychlinsky Cell Activation and Apoptosis by Bacterial Lipoproteins Through Toll-like Receptor-2 Science, July 30, 1999; 285(5428): 736 - 739. [Abstract] [Full Text]
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R. I. Tapping, S. L. Orr, E. M. Lawson, K. Soldau, and P. S. Tobias Membrane-Anchored Forms of Lipopolysaccharide (LPS)-Binding Protein Do Not Mediate Cellular Responses to LPS Independently of CD14 J. Immunol., May 1, 1999; 162(9): 5483 - 5489. [Abstract] [Full Text] [PDF]
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S. Sugawara, R. Arakaki, H. Rikiishi, and H. Takada Lipoteichoic Acid Acts as an Antagonist and an Agonist of Lipopolysaccharide on Human Gingival Fibroblasts and Monocytes in a CD14-Dependent Manner Infect. Immun., April 1, 1999; 67(4): 1623 - 1632. [Abstract] [Full Text] [PDF]
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G. H. Giambartolomei, V. A. Dennis, B. L. Lasater, and M. T. Philipp Induction of Pro- and Anti-Inflammatory Cytokines by Borrelia burgdorferi Lipoproteins in Monocytes Is Mediated by CD14 Infect. Immun., January 1, 1999; 67(1): 140 - 147. [Abstract] [Full Text] [PDF]
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N. W. J. Schroder, D. Pfeil, B. Opitz, K. S. Michelsen, J. Amberger, U. Zahringer, U. B. Gobel, and R. R. Schumann Activation of Mitogen-activated Protein Kinases p42/44, p38, and Stress-activated Protein Kinases in Myelo-monocytic Cells by Treponema Lipoteichoic Acid J. Biol. Chem., March 23, 2001; 276(13): 9713 - 9719. [Abstract] [Full Text] [PDF]
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