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Blood, 15 October 2000, Vol. 96, No. 8, pp. 2784-2792
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Induction of decay-accelerating factor by thrombin through a
protease-activated receptor 1 and protein kinase C-dependent pathway
protects vascular endothelial cells from
complement-mediated injury
Elaine A. Lidington,
Dorian
O. Haskard, and
Justin C. Mason
From the British Heart Foundation Cardiovascular
Medicine Unit, National Heart and Lung Institute, Imperial College
School of Technology and Medicine, Hammersmith Hospital, London,
England.
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- 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 activationis a
physiologic agonist for the PKC-dependent pathway of DAF
regulation, thereby providing a negative feedback loop protecting
against thrombosis in inflammation.
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