Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide

doi:10.1084/jem.188.11.2091

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J. Exp. Med., Volume 188, Number 11, December 7, 1998 2091-2097

Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide

By Carsten J. Kirschning, Holger Wesche, T. Merrill Ayres, and Mike Rothe

From Tularik, Inc., South San Francisco, California 94080

Bacterial lipopolysaccharide (LPS) induces activation of the transcription factor nuclear factor $kappa$ B (NF- $kappa$ B) in host cellsupon infection. LPS binds to the glycosylphosphatidylinositol(GPI)- anchored membrane protein CD14, which lacks an intracellularsignaling domain. Here we investigated the role of mammalian Toll-likereceptors (TLRs) as signal transducers for LPS. Overexpressionof TLR2, but not TLR1, TLR4, or CD14 conferred LPS inducibilityof NF- $kappa$ B activation in mammalian 293 cells. Mutational analysisdemonstrated that this LPS response requires the intracellulardomain of TLR2. LPS signaling through TLR2 was dependent on serumwhich contains soluble CD14 (sCD14). Coexpression of CD14 synergisticallyenhanced LPS signal transmission through TLR2. In addition, purifiedrecombinant sCD14 could substitute for serum to support LPS-inducedTLR2 activation. LPS stimulation of TLR2 initiated an interleukin1 receptor-like NF- $kappa$ B signaling cascade. These findings suggestthat TLR2 may be a signaling component of a cellular receptorfor LPS.

Key words: lipopolysaccharide; CD14; interleukin 1 receptor; nuclear factor $kappa$ B; signal transduction

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Li, C., Wang, Y., Gao, L., Zhang, J., Shao, J., Wang, S., Feng, W., Wang, X., Li, M., Chang, Z. (2002). Expression of Toll-like Receptors 2 and 4 and CD14 during Differentiation of HL-60 Cells Induced by Phorbol 12-Myristate 13-Acetate and 1{alpha}, 25-Dihydroxy-Vitamin D3. Cell Growth Differ. 13: 27-38 [Abstract] [Full Text]
Wang, T., Lafuse, W. P., Zwilling, B. S. (2001). NF{kappa}B and Sp1 Elements Are Necessary for Maximal Transcription of Toll-like Receptor 2 Induced by Mycobacterium avium. J. Immunol. 167: 6924-6932 [Abstract] [Full Text]
Schaeffer, L. M., Weiss, A. A. (2001). Pertussis Toxin and Lipopolysaccharide Influence Phagocytosis of Bordetella pertussis by Human Monocytes. Infect. Immun. 69: 7635-7641 [Abstract] [Full Text]
McCurdy, J. D., Lin, T.-J., Marshall, J. S. (2001). Toll-like receptor 4-mediated activation of murine mast cells. J. Leukoc. Biol. 70: 977-984 [Abstract] [Full Text]
Neilsen, P. O., Zimmerman, G. A., McIntyre, T. M. (2001). Escherichia coli Braun Lipoprotein Induces a Lipopolysaccharide-Like Endotoxic Response from Primary Human Endothelial Cells. J. Immunol. 167: 5231-5239 [Abstract] [Full Text]
Stenger, S, Rollinghoff, M (2001). Role of cytokines in the innate immune response to intracellular pathogens. Ann Rheum Dis 60: iii43-46 [Full Text]
Diks, S. H., van Deventer, S. J.H., Peppelenbosch, M. P. (2001). Invited review: Lipopolysaccharide recognition, internalisation, signalling and other cellular effects. Innate Immunity 7: 335-348 [Abstract]
Prebeck, S., Kirschning, C., Durr, S., da Costa, C., Donath, B., Brand, K., Redecke, V., Wagner, H., Miethke, T. (2001). Predominant Role of Toll-Like Receptor 2 Versus 4 in Chlamydia pneumoniae-Induced Activation of Dendritic Cells. J. Immunol. 167: 3316-3323 [Abstract] [Full Text]
Ohnishi, T., Muroi, M., Tanamoto, K.-i. (2001). N-Linked Glycosylations at Asn26 and Asn114 of Human MD-2 Are Required for Toll-Like Receptor 4-Mediated Activation of NF-{kappa}B by Lipopolysaccharide. J. Immunol. 167: 3354-3359 [Abstract] [Full Text]
Sun, D., Muthukumar, A. R., Lawrence, R. A., Fernandes, G. (2001). Effects of Calorie Restriction on Polymicrobial Peritonitis Induced by Cecum Ligation and Puncture in Young C57BL/6 Mice. CVI 8: 1003-1011 [Abstract] [Full Text]
Smiley, S. T., King, J. A., Hancock, W. W. (2001). Fibrinogen Stimulates Macrophage Chemokine Secretion Through Toll-Like Receptor 4. J. Immunol. 167: 2887-2894 [Abstract] [Full Text]
Medvedev, A. E., Henneke, P., Schromm, A., Lien, E., Ingalls, R., Fenton, M. J., Golenbock, D. T., Vogel, S. N. (2001). 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. 167: 2257-2267 [Abstract] [Full Text]
Aliprantis, A. O., Weiss, D. S., Zychlinsky, A. (2001). Toll-like receptor-2 transduces signals for NF-{kappa}B activation, apoptosis and reactive oxygen species production. Innate Immunity 7: 287-291 [Abstract]
Muzio, M., Mantovani, A. (2001). Toll-like receptors (TLRs) signalling and expression pattern. Innate Immunity 7: 297-300 [Abstract]
Schromm, A. B., Lien, E., Henneke, P., Chow, J. C., Yoshimura, A., Heine, H., Latz, E., Monks, B. G., Schwartz, D. A., Miyake, K., Golenbock, D. T. (2001). Molecular Genetic Analysis of an Endotoxin Nonresponder Mutant Cell Line: A Point Mutation in a Conserved Region of MD-2 Abolishes Endotoxin-induced Signaling. J. Exp. Med. 194: 79-88 [Abstract] [Full Text]