The serine protease inhibitor antithrombin III inhibits LPS-mediated NF-kappaB activation by TLR-4

• Published in: FEBS letters Vol. 508; no. 3; pp. 313 - 317
• Main Authors: Mansell, A, Reinicke, A, Worrall, D M, O'Neill, L A
• Format: Journal Article
• Language: English
• Published: England 23.11.2001
• Subjects: Antithrombin III - pharmacology; Cell Line; Drosophila Proteins; Enzyme Activation; Hirudins - pharmacology; Humans; Lipid A - pharmacology; Lipopolysaccharides - pharmacology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Monocytes; NF-kappa B - metabolism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors - pharmacology; Signal Transduction; Toll-Like Receptor 4; Toll-Like Receptors
• ISSN: 0014-5793; 1873-3468

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.