benzyloxycarbonyl-isoleucyl-glutamyl(o-tert-butyl)-alanyl-leucinal and Inflammation

There is increasing evidence for functional crosstalk between inflammatory and thrombotic pathways in inflammatory vascular diseases such as atherosclerosis and vasculitis. Thus, complement activation on the endothelial cell (EC) surface during inflammation may generate thrombin via the synthesis of tissue factor. We explored the hypothesis that thrombin induces EC expression of the complement-regulatory proteins decay-accelerating factor (DAF), membrane cofactor protein (MCP), and CD59 and that this maintains vascular integrity during coagulation associated with complement activation. Thrombin increased DAF expression on the surface of ECs by 4-fold in a dose- and time-dependent manner as measured by flow cytometry. DAF up-regulation was first detectable at 6 hours and maximal 24 hours poststimulation, whereas no up-regulation of CD59 or MCP was seen. Thrombin-induced expression required increased DAF messenger RNA and de novo protein synthesis. The response depended on activation of protease-activated receptor 1 (PAR1) and was inhibited by pharmacologic antagonists of protein kinase C (PKC), p38 and p42/44 mitogen-activated protein kinase, and nuclear factor-kappa B. The increased DAF expression was functionally relevant because it significantly reduced C3 deposition and complement-mediated EC lysis. Thus, thrombin-generated at inflammatory sites in response to complement activation-is a physiologic agonist for the PKC-dependent pathway of DAF regulation, thereby providing a negative feedback loop protecting against thrombosis in inflammation. (Blood. 2000;96:2784-2792)

Topics: CD55 Antigens; Cells, Cultured; Complement Activation; Complement System Proteins; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Feedback; Flavonoids; Gene Expression Regulation; Humans; Imidazoles; Indoles; Inflammation; Lymphokines; Maleimides; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; NF-kappa B; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Protein Kinase C; Protein Serine-Threonine Kinases; Pyridines; Receptor, PAR-1; Receptors, Thrombin; Recombinant Proteins; RNA, Messenger; Thrombin; Thrombosis; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors