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* Department of Medical Sciences and
Department of Medicine, McMaster University, and
Henderson Research Centre, Hamilton, Ontario, Canada
The protective effect of recombinant activated protein C therapy in patients with severe sepsis likely reflects the ability of recombinant activated protein C to modulate multiple pathways implicated in sepsis pathophysiology. In this study, we examined the effects of recombinant activated protein C on the anti-inflammatory cytokine IL-10 and on the procoagulant molecule tissue factor (TF) in LPS-challenged blood monocytes. Treatment of LPS-stimulated monocytes with recombinant activated protein C resulted in an up-regulation of IL-10 protein production and mRNA synthesis. The up-regulation of IL-10 required the serine protease activity of recombinant activated protein C and was dependent on protease-activated receptor-1, but was independent of the endothelial protein C receptor. At the intracellular level, p38 MAPK activation was required for recombinant activated protein C-mediated up-regulation of IL-10. We further observed that incubation of LPS-stimulated monocytes with recombinant activated protein C down-regulated TF Ag and activity levels. This anticoagulant effect of recombinant activated protein C was dependent on IL-10 since neutralization of endogenously produced IL-10 abrogated the effect. In patients with severe sepsis, plasma IL-10 levels were markedly higher in those treated with recombinant activated protein C than in those who did not receive recombinant activated protein C. This study reveals novel regulatory functions of recombinant activated protein C, specifically the up-regulation of IL-10 and the inhibition of TF activity in monocytes. Our data further suggest that these activities of recombinant activated protein C are directly linked: the recombinant activated protein C-mediated up-regulation of IL-10 reduces TF in circulating monocytes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part grants-in-aid from the Canadian Institutes of Health Research (Grant MOP-57790) and the National Cancer Institute of Canada (Grant 018289), by a Canadian Institutes of Health Research Team Grant (Grant MOP-CTP79846), and by a Premier’s Research Excellence Award. P.C.L. is a recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada. Funding for L.J.T. was provided in part by a Natural Science and Engineering Research Council Canada Graduate Scholarship and by a scholarship from Hemostasis Reference Laboratories Inc.
L.J.T. performed most of the experiments, contributed to study design and data analysis, and wrote the paper. S.B. performed some of the experiments and data analysis. P.C.L. supervised the project, contributed to study design and data analysis, and wrote the paper.
2 Address correspondence and reprint requests to Dr. Patricia Liaw, Henderson Research Centre, 711 Concession Street, Hamilton, Ontario, L8V 1C3, Canada. E-mail address: pliaw{at}thrombosis.hhscr.org
3 Abbreviations used in this paper: TF, tissue factor; EPCR, endothelial protein C receptor; PPACK, phe-pro-arg-chloromethylketone; PAR-1, protease-activated receptor-1.
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