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

In Drosophila, the Toll family of proteins mediates the innate immune respo nse. Toll is activated by Spaetzle, which is generated in response to patho gens via a serine protease cascade. We wished to investigate if lipopolysac charides (LPS) might activate Toll-like receptor (TLR) 4 via a scrine prote ase in humans. The serpin antithrombin III (ATIII) and the thrombin inhibit or 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 tha t LPS may activate a mammalian serine protease, which generates a product r equired for TLR4 signalling. (C) 2001 Federation of European Biochemical So cieties. Published by Elsevier Science B.V. All rights reserved.