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Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling

Nature volume 395, pages 284–288 (1998)Cite this article

Abstract

Vertebrates and invertebrates initiate a series of defence mechanisms following infection by Gram-negative bacteria by sensing the presence of lipopolysaccharide (LPS), a major component of the cell wall of the invading pathogen1. In humans, monocytes and macrophages respond to LPS by inducing the expression of cytokines, cell-adhesion proteins, and enzymes involved in the production of small proinflammatory mediators. Under pathophysiological conditions, LPS exposure can lead to an often fatal syndrome known as septic shock2. Sensitive responses of myeloid cells to LPS require a plasma protein called LPS-binding protein and the glycosylphosphatidylinositol-anchored membrane protein CD14. However, the mechanism by which the LPS signal is transduced across the plasma membrane remains unknown3. Here we show that Toll-like receptor 2 (TLR2) is a signalling receptor that is activated by LPS in a response that depends on LPS-binding protein and is enhanced by CD14. A region in the intracellular domain of TLR2 with homology to a portion of the interleukin (IL)-1 receptor that is implicated in the activation of the IL-1–receptor-associated kinase is required for this response. Our results indicate that TLR2 is a direct mediator of signalling by LPS.

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Figure 1: Expression pattern of TLR2.
Figure 2: TLR2 mediates LPS-induced signalling.
Figure 3: Domain function of TLR2 in signalling.
Figure 4: High potency of E.coli K12 LPS (LCD25) and its binding to TLR2.
Figure 5: Activation of TLR2 by LPS in 293 cells results in induction of IL-8 mRNA expression.

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Acknowledgements

We thank our colleagues at Genentech, in particular members of the SPDI team, for helpful and invigorating discussions, and the oligonucleotide synthesis group for the preparation of synthetic DNA.

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  1. Department of Molecular Biology, Genentech, South San Francisco, 94080-4990, California, USA

    Ruey-Bing Yang, Melanie R. Mark, Alane Gray, Arthur Huang, Ming Hong Xie, Min Zhang, Audrey Goddard, William I. Wood, Austin L. Gurney & Paul J. Godowski

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Correspondence to Paul J. Godowski.

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Yang, RB., Mark, M., Gray, A. et al. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 395, 284–288 (1998). https://doi.org/10.1038/26239

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