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

• Published in: FEBS letters Vol. 508; no. 3; pp. 313 - 317
• Main Authors: Mansell, Ashley, Reinicke, Anna, Worrall, D.Margaret, O’Neill, Luke A.J
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 23.11.2001
• Subjects: ATIII, antithrombin III; EMSA, electrophoretic mobility shift assay; IL-1, interleukin-1; Inflammation; L-ATIII, latent antithrombin III; Lipopolysaccharide; LPS, lipopolysaccharide; Monocyte; Signal transduction; TLR, Toll-like receptor; TNF, tumour necrosis factor; Transcription factor; ATIII, antithrombin III; Signal transduction; TLR, Toll-like receptor; Monocyte; TNF, tumour necrosis factor; Lipopolysaccharide; L-ATIII, latent antithrombin III; LPS, lipopolysaccharide; Inflammation; IL-1, interleukin-1; Transcription factor; EMSA, electrophoretic mobility shift assay
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(01)03077-0

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)-κB activation by LPS and Lipid A. ATIII and hirudin were also able to inhibit LPS-induced NF-κB 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.