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*
The Pulmonary Center, Boston University School of Medicine, Boston, MA 02118; and
Infectious Disease Section, Boston Medical Center, Boston, MA 02118
Mammalian Toll-like receptor (TLR) proteins are new members of the IL-1 receptor family that participate in activation of cells by bacteria and bacterial products. Several recent reports indicate that TLR proteins mediate cellular activation by bacterial LPS via a signaling pathway that is largely shared by the type I IL-1 receptor. We previously showed that Chinese hamster ovary (CHO) fibroblasts engineered to express CD14 (CHO/CD14) were responsive to LPS, but not to a distinct CD14 ligand, mycobacterial lipoarabinomannan (LAM). These CHO/CD14 cells were subsequently found to possess a frame-shift mutation within the TLR2 gene which resulted in their inability to express functional TLR2 protein. Thus, we hypothesized that TLR2, but not TLR4, was necessary for LAM signaling. In this paper we show that CHO/CD14 cells engineered to express functional TLR2 protein acquired the ability to be activated by LAM. Similarly, overexpression of TLR2 in murine macrophages conferred enhanced LAM responsiveness. Together, our data demonstrate that the distinct CD14 ligands LAM and LPS utilize different TLR proteins to initiate intracellular signals. These findings suggest a novel receptor signaling paradigm in which the binding of distinct ligands is mediated by a common receptor chain, but cellular activation is initiated via distinct signal-transducing chains that confer ligand specificity. This paradigm contrasts with many cytokine receptor complexes in which receptor specificity is conferred by a unique ligand-binding chain but cellular activation is initiated via shared signal-transducing chains.
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T. H. Flo, L. Ryan, E. Latz, O. Takeuchi, B. G. Monks, E. Lien, O. Halaas, S. Akira, G. Skjak-Brak, D. T. Golenbock, et al. Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers J. Biol. Chem., September 13, 2002; 277(38): 35489 - 35495. [Abstract] [Full Text] [PDF]
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 E. A. Kurt-Jones, L. Mandell, C. Whitney, A. Padgett, K. Gosselin, P. E. Newburger, and R. W. Finberg Role of Toll-like receptor 2 (TLR2) in neutrophil activation: GM-CSF enhances TLR2 expression and TLR2-mediated interleukin 8 responses in neutrophils Blood, August 13, 2002; 100(5): 1860 - 1868. [Abstract] [Full Text] [PDF]
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V. S. Carl, K. Brown-Steinke, M. J. H. Nicklin, and M. F. Smith Jr. Toll-like Receptor 2 and 4 (TLR2 and TLR4) Agonists Differentially Regulate Secretory Interleukin-1 Receptor Antagonist Gene Expression in Macrophages J. Biol. Chem., May 10, 2002; 277(20): 17448 - 17456. [Abstract] [Full Text] [PDF]
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J. Hellman, J. D. Roberts Jr., M. M. Tehan, J. E. Allaire, and H. S. Warren Bacterial Peptidoglycan-associated Lipoprotein Is Released into the Bloodstream in Gram-negative Sepsis and Causes Inflammation and Death in Mice J. Biol. Chem., April 12, 2002; 277(16): 14274 - 14280. [Abstract] [Full Text] [PDF]
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R. van Crevel, T. H. M. Ottenhoff, and J. W. M. van der Meer Innate Immunity to Mycobacterium tuberculosis Clin. Microbiol. Rev., April 1, 2002; 15(2): 294 - 309. [Abstract] [Full Text] [PDF]
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J. J. Watters, J. A. Sommer, Z. A. Pfeiffer, U. Prabhu, A. N. Guerra, and P. J. Bertics A Differential Role for the Mitogen-activated Protein Kinases in Lipopolysaccharide Signaling. THE MEK/ERK PATHWAY IS NOT ESSENTIAL FOR NITRIC OXIDE AND INTERLEUKIN 1beta PRODUCTION J. Biol. Chem., March 8, 2002; 277(11): 9077 - 9087. [Abstract] [Full Text] [PDF]
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T. Vasselon and P. A. Detmers Toll Receptors: a Central Element in Innate Immune Responses Infect. Immun., March 1, 2002; 70(3): 1033 - 1041. [Full Text] [PDF]
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A. Yoshimura, T. Kaneko, Y. Kato, D. T. Golenbock, and Y. Hara Lipopolysaccharides from Periodontopathic Bacteria Porphyromonas gingivalis and Capnocytophaga ochracea Are Antagonists for Human Toll-Like Receptor 4 Infect. Immun., January 1, 2002; 70(1): 218 - 225. [Abstract] [Full Text] [PDF]
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P. Henneke, O. Takeuchi, J. A. van Strijp, H.-K. Guttormsen, J. A. Smith, A. B. Schromm, T. A. Espevik, S. Akira, V. Nizet, D. L. Kasper, et al. Novel Engagement of CD14 and Multiple Toll-Like Receptors by Group B Streptococci J. Immunol., December 15, 2001; 167(12): 7069 - 7076. [Abstract] [Full Text] [PDF]
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P. I. Song, T. A. Abraham, Y. Park, A. S. Zivony, B. Harten, H. F. Edelhauser, S. L. Ward, C. A. Armstrong, and J. C. Ansel The Expression of Functional LPS Receptor Proteins CD14 And Toll-Like Receptor 4 in Human Corneal Cells Invest. Ophthalmol. Vis. Sci., November 1, 2001; 42(12): 2867 - 2877. [Abstract] [Full Text] [PDF]
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B. Pulendran, P. Kumar, C. W. Cutler, M. Mohamadzadeh, T. Van Dyke, and J. Banchereau Lipopolysaccharides from Distinct Pathogens Induce Different Classes of Immune Responses In Vivo J. Immunol., November 1, 2001; 167(9): 5067 - 5076. [Abstract] [Full Text] [PDF]
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 B W Jones, K A Heldwein, T K Means, J J Saukkonen, and M J Fenton Differential roles of Toll-like receptors in the elicitation of proinflammatory responses by macrophages Ann Rheum Dis, November 1, 2001; 60(90003): iii6 - 12. [Abstract] [Full Text] [PDF]
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I. C. Almeida and R. T. Gazzinelli Proinflammatory activity of glycosylphosphatidylinositol anchors derived from Trypanosoma cruzi: structural and functional analyses J. Leukoc. Biol., October 1, 2001; 70(4): 467 - 477. [Abstract] [Full Text] [PDF]
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A. Schonemeyer, R. Lucius, B. Sonnenburg, N. Brattig, R. Sabat, K. Schilling, J. Bradley, and S. Hartmann Modulation of Human T Cell Responses and Macrophage Functions by Onchocystatin, a Secreted Protein of the Filarial Nematode Onchocerca volvulus J. Immunol., September 15, 2001; 167(6): 3207 - 3215. [Abstract] [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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S. Sugawara, S. Yang, K. Iki, J. Hatakeyama, R. Tamai, O. Takeuchi, S. Akashi, T. Espevik, S. Akira, and H. Takada Monocytic Cell Activation by Nonendotoxic Glycoprotein from Prevotella intermedia ATCC 25611 Is Mediated by Toll-Like Receptor 2 Infect. Immun., August 1, 2001; 69(8): 4951 - 4957. [Abstract] [Full Text] [PDF]
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C. Neufert, R. K. Pai, E. H. Noss, M. Berger, W. H. Boom, and C. V. Harding Mycobacterium tuberculosis 19-kDa Lipoprotein Promotes Neutrophil Activation J. Immunol., August 1, 2001; 167(3): 1542 - 1549. [Abstract] [Full Text] [PDF]
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M. T. Abreu, P. Vora, E. Faure, L. S. Thomas, E. T. Arnold, and M. Arditi Decreased Expression of Toll-Like Receptor-4 and MD-2 Correlates with Intestinal Epithelial Cell Protection Against Dysregulated Proinflammatory Gene Expression in Response to Bacterial Lipopolysaccharide J. Immunol., August 1, 2001; 167(3): 1609 - 1616. [Abstract] [Full Text] [PDF]
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O. Takeuchi, T. Kawai, P. F. Muhlradt, M. Morr, J. D. Radolf, A. Zychlinsky, K. Takeda, and S. Akira Discrimination of bacterial lipoproteins by Toll-like receptor 6 Int. Immunol., July 1, 2001; 13(7): 933 - 940. [Abstract] [Full Text] [PDF]
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J. Nigou, C. Zelle-Rieser, M. Gilleron, M. Thurnher, and G. Puzo Mannosylated Lipoarabinomannans Inhibit IL-12 Production by Human Dendritic Cells: Evidence for a Negative Signal Delivered Through the Mannose Receptor J. Immunol., June 15, 2001; 166(12): 7477 - 7485. [Abstract] [Full Text] [PDF]
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B. W. Jones, T. K. Means, K. A. Heldwein, M. A. Keen, P. J. Hill, J. T. Belisle, and M. J. Fenton Different Toll-like receptor agonists induce distinct macrophage responses J. Leukoc. Biol., June 1, 2001; 69(6): 1036 - 1044. [Abstract] [Full Text] [PDF]
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A. A. Chackerian, T. V. Perera, and S. M. Behar Gamma Interferon-Producing CD4+ T Lymphocytes in the Lung Correlate with Resistance to Infection with Mycobacterium tuberculosis Infect. Immun., April 1, 2001; 69(4): 2666 - 2674. [Abstract] [Full Text] [PDF]
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S. Shoham, C. Huang, J.-M. Chen, D. T. Golenbock, and S. M. Levitz Toll-Like Receptor 4 Mediates Intracellular Signaling Without TNF-{{alpha}} Release in Response to Cryptococcus neoformans Polysaccharide Capsule J. Immunol., April 1, 2001; 166(7): 4620 - 4626. [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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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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 G.A.W. Rook, G. Seah, and A. Ustianowski M. tuberculosis: immunology and vaccination Eur. Respir. J., March 1, 2001; 17(3): 537 - 557. [Abstract] [Full Text] [PDF]
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T. H. Flo, O. Halaas, S. Torp, L. Ryan, E. Lien, B. Dybdahl, A. Sundan, and T. Espevik Differential expression of Toll-like receptor 2 in human cells J. Leukoc. Biol., March 1, 2001; 69(3): 474 - 481. [Abstract] [Full Text]
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T. Kikuchi, T. Matsuguchi, N. Tsuboi, A. Mitani, S. Tanaka, M. Matsuoka, G. Yamamoto, T. Hishikawa, T. Noguchi, and Y. Yoshikai Gene Expression of Osteoclast Differentiation Factor Is Induced by Lipopolysaccharide in Mouse Osteoblasts Via Toll-Like Receptors J. Immunol., March 1, 2001; 166(5): 3574 - 3579. [Abstract] [Full Text] [PDF]
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D. Chakravortty, Y. Kato, T. Sugiyama, N. Koide, M. M. Mu, T. Yoshida, and T. Yokochi Inhibition of p38 Mitogen-Activated Protein Kinase Augments Lipopolysaccharide-Induced Cell Proliferation in CD14-Expressing Chinese Hamster Ovary Cells Infect. Immun., February 1, 2001; 69(2): 931 - 936. [Abstract] [Full Text] [PDF]
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G. R. Strohmeier, J. H. Walsh, E. S. Klings, H. W. Farber, W. W. Cruikshank, D. M. Center, and M. J. Fenton Lipopolysaccharide Binding Protein Potentiates Airway Reactivity in a Murine Model of Allergic Asthma J. Immunol., February 1, 2001; 166(3): 2063 - 2070. [Abstract] [Full Text] [PDF]
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A. M. Hajjar, D. S. O'Mahony, A. Ozinsky, D. M. Underhill, A. Aderem, S. J. Klebanoff, and C. B. Wilson Cutting Edge: Functional Interactions Between Toll-Like Receptor (TLR) 2 and TLR1 or TLR6 in Response to Phenol-Soluble Modulin J. Immunol., January 1, 2001; 166(1): 15 - 19. [Abstract] [Full Text] [PDF]
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S. Tsuji, M. Matsumoto, O. Takeuchi, S. Akira, I. Azuma, A. Hayashi, K. Toyoshima, and T. Seya Maturation of Human Dendritic Cells by Cell Wall Skeleton of Mycobacterium bovis Bacillus Calmette-Guerin: Involvement of Toll-Like Receptors Infect. Immun., December 1, 2000; 68(12): 6883 - 6890. [Abstract] [Full Text] [PDF]
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E. Cario and D. K. Podolsky Differential Alteration in Intestinal Epithelial Cell Expression of Toll-Like Receptor 3 (TLR3) and TLR4 in Inflammatory Bowel Disease Infect. Immun., December 1, 2000; 68(12): 7010 - 7017. [Abstract] [Full Text] [PDF]
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T. Matsuguchi, T. Musikacharoen, T. Ogawa, and Y. Yoshikai Gene Expressions of Toll-Like Receptor 2, But Not Toll-Like Receptor 4, Is Induced by LPS and Inflammatory Cytokines in Mouse Macrophages J. Immunol., November 15, 2000; 165(10): 5767 - 5772. [Abstract] [Full Text] [PDF]
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R. I. Tapping, S. Akashi, K. Miyake, P. J. Godowski, and P. S. Tobias Toll-Like Receptor 4, But Not Toll-Like Receptor 2, Is a Signaling Receptor for Escherichia and Salmonella Lipopolysaccharides J. Immunol., November 15, 2000; 165(10): 5780 - 5787. [Abstract] [Full Text] [PDF]
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M. Fujihara, S. Wakamoto, T. Ito, M. Muroi, T. Suzuki, H. Ikeda, and K. Ikebuchi Lipopolysaccharide-triggered desensitization of TNF-{alpha} mRNA expression involves lack of phosphorylation of I{kappa}B{alpha} in a murine macrophage-like cell line, P388D1 J. Leukoc. Biol., August 1, 2000; 68(2): 267 - 276. [Abstract] [Full Text]
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