Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2.
The life-threatening complications of sepsis in humans are elicited by infection with Gram-negative as well as Gram-positive bacteria. Recently, lipopolysaccharide (LPS), a major biologically active agent of Gram-negative bacteria, was shown to mediate cellular activation by a member of the human Toll-like receptor family, Toll-like receptor (TLR) 2. Here we investigate the mechanism of cellular activation by soluble peptidoglycan (sPGN) and lipoteichoic acid (LTA), main stimulatory components of Gram-positive bacteria. Like LPS, sPGN and LTA bind to the glycosylphosphatidylinositol-anchored membrane protein CD14 and induce activation of the transcription factor NF-kappaB in host cells like macrophages. We show that whole Gram-positive bacteria, sPGN and LTA induce the activation of NF-kappaB in HEK293 cells expressing TLR2 but not in cells expressing TLR1 or TLR4. The sPGN- and LTA-induced NF-kappaB activation was not inhibited by polymyxin B, an antibiotic that binds and neutralizes LPS. Coexpression together with membrane CD14 enhances sPGN signal transmission through TLR2. In contrast to LPS signaling, activation of TLR2 by sPGN and LTA does not require serum. These findings identify TLR2 as a signal transducer for sPGN and LTA in addition to LPS.
Schwandner
R
R
Tularik Inc., South San Francisco, California 94080, USA.
Dziarski
R
R
Wesche
H
H
Rothe
M
M
Kirschning
C J
CJ
D002460:Cell Line; D029721:Drosophila Proteins; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000378:metabolism; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology*; D011112:Polymyxin B / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D013682:Teichoic Acids / Q000494:pharmacology*; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015533:Transcriptional Activation
D029721:Drosophila Proteins; D017261:Glycosylphosphatidylinositols; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D013682:Teichoic Acids; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C009900:lipoteichoic acid; D011112:Polymyxin B