The serine protease inhibitor antithrombin III inhibits LPS-mediated NF-kappaB activation by TLR-4.
In Drosophila, the Toll family of proteins mediates the innate immune response. Toll is activated by Spaetzle, which is generated in response to pathogens via a serine protease cascade. We wished to investigate if lipopolysaccharides (LPS) might activate Toll-like receptor (TLR) 4 via a serine protease in humans. The serpin antithrombin III (ATIII) and the thrombin inhibitor hirudin both inhibited nuclear factor (NF)-kappaB activation by LPS and Lipid A. ATIII and hirudin were also able to inhibit LPS-induced NF-kappaB activation in cells stably transfected with TLR4. These results suggest that LPS may activate a mammalian serine protease, which generates a product required for TLR4 signalling.
Mansell
A
A
Department of Biochemistry, Trinity College Dublin, Ireland.
Reinicke
A
A
Worrall
D M
DM
O'Neill
L A
LA
D000990:Antithrombin III / Q000494:pharmacology*; D002460:Cell Line; D029721:Drosophila Proteins; D004789:Enzyme Activation; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D008050:Lipid A / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes; D016328:NF-kappa B / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D006629:Hirudins; D008050:Lipid A; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D015842:Serine Proteinase Inhibitors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000990:Antithrombin III; D012697:Serine Endopeptidases