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*
Division of Cell Biology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132; and
Merck Research Laboratories, Rahway, NJ 07065
Borrelia burgdorferi possesses membrane lipoproteins
that exhibit stimulatory properties and, consequently, have been
implicated in the pathology related to Lyme disease. As CD14 has been
shown to mediate signaling by a number of lipid-modified bacterial
products, the involvement of CD14 in signaling mediated by two B.
burgdorferi lipoproteins, outer surface protein A (OspA) and
OspC, was determined. Lipoprotein-mediated induction of nuclear
factor-
B nuclear translocation and production of IL-8 and IL-6 in
HUVEC was enhanced in the presence of serum or soluble rCD14.
CD14-specific Abs that block LPS-mediated signaling also inhibited
lipoprotein-dependent signaling in HUVEC and neutrophils. The formation
of stable complexes between OspA and CD14 was demonstrated by native
gel electrophoresis. LPS was found to compete with OspA for binding
with CD14, suggesting that LPS and OspA bind similar regions on CD14.
The similarity in binding was further supported by the finding that a
mutant soluble CD14, lacking the LPS binding site, did not facilitate
lipoprotein signaling, nor did it form a complex with OspA. Binding of
OspA to CD14 was dependent on the lipid modification, as unlipidated
OspA did not form a complex with CD14 or stimulate cells. In contrast,
the lipopeptide remaining after proteinase K digestion both formed a
complex with CD14 and retained stimulatory properties. These findings
indicate that CD14 facilitates bacterial lipoprotein signaling in
mammalian cells.
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M. D. Cunningham, R. A. Shapiro, C. Seachord, K. Ratcliffe, L. Cassiano, and R. P. Darveau CD14 Employs Hydrophilic Regions to ""Capture"" Lipopolysaccharides J. Immunol., March 15, 2000; 164(6): 3255 - 3263. [Abstract] [Full Text] [PDF]
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A. M. Soler-Rodriguez, H. Zhang, H. S. Lichenstein, N. Qureshi, D. W. Niesel, S. E. Crowe, J. W. Peterson, and G. R. Klimpel Neutrophil Activation by Bacterial Lipoprotein Versus Lipopolysaccharide: Differential Requirements for Serum and CD14 J. Immunol., March 1, 2000; 164(5): 2674 - 2683. [Abstract] [Full Text] [PDF]
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I. G. Scragg, D. Kwiatkowski, V. Vidal, A. Reason, T. Paxton, M. Panico, A. Dell, and H. Morris Structural Characterization of the Inflammatory Moiety of a Variable Major Lipoprotein of Borrelia recurrentis J. Biol. Chem., January 14, 2000; 275(2): 937 - 941. [Abstract] [Full Text] [PDF]
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 Z. Hmama, D. Nandan, L. Sly, K. L. Knutson, P. Herrera-Velit, and N. E. Reiner 1{alpha},25-Dihydroxyvitamin D3-Induced Myeloid Cell Differentiation Is Regulated by a Vitamin D Receptor-Phosphatidylinositol 3-Kinase Signaling Complex J. Exp. Med., December 6, 1999; 190(11): 1583 - 1594. [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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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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J. Talkington and S. P. Nickell Borrelia burgdorferi Spirochetes Induce Mast Cell Activation and Cytokine Release Infect. Immun., March 1, 1999; 67(3): 1107 - 1115. [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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