The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/12/2091/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 11, December 7, 1998 2091-2097

Articles

Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide

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 cells upon infection. LPS binds to the glycosylphosphatidylinositol (GPI)- anchored membrane protein CD14, which lacks an intracellular signaling domain. Here we investigated the role of mammalian Toll-like receptors (TLRs) as signal transducers for LPS. Overexpression of TLR2, but not TLR1, TLR4, or CD14 conferred LPS inducibility of NF-{kappa}B activation in mammalian 293 cells. Mutational analysis demonstrated that this LPS response requires the intracellular domain of TLR2. LPS signaling through TLR2 was dependent on serum which contains soluble CD14 (sCD14). Coexpression of CD14 synergistically enhanced LPS signal transmission through TLR2. In addition, purified recombinant sCD14 could substitute for serum to support LPS-induced TLR2 activation. LPS stimulation of TLR2 initiated an interleukin 1 receptor–like NF-{kappa}B signaling cascade. These findings suggest that TLR2 may be a signaling component of a cellular receptor for LPS.

Key Words: lipopolysaccharide • CD14 • interleukin 1 receptor • nuclear factor {kappa}B • signal transduction

Address correspondence to Mike Rothe, Tularik, Inc., Two Corporate Dr., South San Francisco, CA 94080. Phone: 650-829-4450; Fax: 650-829-4400; E-mail: rothe{at}tularik.com

Abbreviations used: EMSA, electrophoretic mobility shift assay; GNDF, glial cell line–derived neurotrophic factor; GPI, glycosylphosphatidylinositol; IKK, I{kappa}B kinase; LBP, LPS binding protein; MAP kinase, mitogen-activated protein kinase; NF-{kappa}B, nuclear factor {kappa}B; NIK, NF-{kappa}B–inducing kinase; RT, reverse transcription; sCD14, soluble CD14; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor.


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