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, Signal Transduction1
*
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and
Maxwell Finland Laboratory for Infectious Diseases, Boston University School of Medicine, Boston Medical Center, Boston, MA 02118
Gram-negative bacterial LPS is a potent activator of inflammatory
responses. The binding of LPS to CD14 initiates signal transduction;
however, the molecular processes immediately following this event
remain unclear. We engineered an LPS-inducible fibroblast reporter cell
line to facilitate the use of molecular genetic techniques to study the
LPS signaling pathway. A plasmid containing the human Tac Ag cDNA under
transcriptional control of the human E selectin promoter was
cotransfected into Chinese hamster ovary (CHO)-K1 cells together with a
CD14 expression plasmid. A cell line was obtained, 3E10, which
up-regulated expression of Tac following stimulation with LPS. Pools of
mutagenized cells were exposed to LPS and then labeled with
anti-Tac mAb. Cells that failed to up-regulate Tac expression were
enriched by flow cytometry. Thirty clonal mutant cell lines were
identified that continued to express CD14 and bind LPS, but failed to
express Tac or translocate nuclear factor-
B (NF-B) following LPS
exposure. TNF-
-treated mutant cells continued to express Tac and
translocate NF-B. An analysis of LPS-induced NF-B activity in
heterokaryons derived from polyethylene glycol-fused cell lines
indicated that recessive mutations in genes encoding components of the
LPS signaling pathway accounted for the signaling defects. To date, two
complementation groups have been identified from 11 cell lines
analyzed. These data demonstrate that the TNF- signaling pathway
diverges from the LPS pathway early in the signal-transduction cascade
despite similarities in LPS- and TNF--induced responses.
Identification of the genes affected in these mutant reporter cells
should identify heretofore-elusive components of the LPS signaling
cascade.
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T. K. Means, B. W. Jones, A. B. Schromm, B. A. Shurtleff, J. A. Smith, J. Keane, D. T. Golenbock, S. N. Vogel, and M. J. Fenton Differential Effects of a Toll-Like Receptor Antagonist on Mycobacterium tuberculosis-Induced Macrophage Responses J. Immunol., March 15, 2001; 166(6): 4074 - 4082. [Abstract] [Full Text] [PDF]
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A. Yoshimura, H. Takada, T. Kaneko, I. Kato, D. Golenbock, and Y. Hara Structural requirements of muramylpeptides for induction of Toll-like receptor 2-mediated NF-{kappa}B activation in CHO cells Innate Immunity, October 1, 2000; 6(5): 407 - 410. [Abstract] [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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A. Kol, A. H. Lichtman, R. W. Finberg, P. Libby, and E. A. Kurt-Jones Cutting Edge: Heat Shock Protein (HSP) 60 Activates the Innate Immune Response: CD14 Is an Essential Receptor for HSP60 Activation of Mononuclear Cells J. Immunol., January 1, 2000; 164(1): 13 - 17. [Abstract] [Full Text] [PDF]
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T. K. Means, E. Lien, A. Yoshimura, S. Wang, D. T. Golenbock, and M. J. Fenton The CD14 Ligands Lipoarabinomannan and Lipopolysaccharide Differ in Their Requirement for Toll-Like Receptors J. Immunol., December 15, 1999; 163(12): 6748 - 6755. [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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T. K. Means, S. Wang, E. Lien, A. Yoshimura, D. T. Golenbock, and M. J. Fenton Human Toll-Like Receptors Mediate Cellular Activation by Mycobacterium tuberculosis J. Immunol., October 1, 1999; 163(7): 3920 - 3927. [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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H. Heine, R. L. Delude, B. G. Monks, T. Espevik, and D. T. Golenbock Bacterial Lipopolysaccharide Induces Expression of the Stress Response Genes hop and H411 J. Biol. Chem., July 23, 1999; 274(30): 21049 - 21055. [Abstract] [Full Text] [PDF]
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A. Yoshimura, E. Lien, R. R. Ingalls, E. Tuomanen, R. Dziarski, and D. Golenbock Cutting Edge: Recognition of Gram-Positive Bacterial Cell Wall Components by the Innate Immune System Occurs Via Toll-Like Receptor 2 J. Immunol., July 1, 1999; 163(1): 1 - 5. [Abstract] [Full Text] [PDF]
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H. Heine, C. J. Kirschning, E. Lien, B. G. Monks, M. Rothe, and D. T. Golenbock Cutting Edge: Cells That Carry A Null Allele for Toll-Like Receptor 2 Are Capable of Responding to Endotoxin J. Immunol., June 15, 1999; 162(12): 6971 - 6975. [Abstract] [Full Text] [PDF]
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E. Lien, J. C. Chow, L. D. Hawkins, P. D. McGuinness, K. Miyake, T. Espevik, F. Gusovsky, and D. T. Golenbock A Novel Synthetic Acyclic Lipid A-like Agonist Activates Cells via the Lipopolysaccharide/Toll-like Receptor 4 Signaling Pathway J. Biol. Chem., January 12, 2001; 276(3): 1873 - 1880. [Abstract] [Full Text] [PDF]
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S. Viriyakosol, P. S. Tobias, R. L. Kitchens, and T. N. Kirkland MD-2 Binds to Bacterial Lipopolysaccharide J. Biol. Chem., October 5, 2001; 276(41): 38044 - 38051. [Abstract] [Full Text] [PDF]
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