Activated protein C up-regulates IL-10 and inhibits tissue factor in blood monocytes.
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.
Toltl
Lisa J
LJ
Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada.
Beaudin
Suzanne
S
Liaw
Patricia C
PC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D000074283:Endothelial Protein C Receptor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D011486:Protein C / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013925:Thromboplastin / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000941:Antigens; D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D008070:Lipopolysaccharides; C478370:PROCR protein, human; D011486:Protein C; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D016753:Interleukin-10; D013925:Thromboplastin; D048051:p38 Mitogen-Activated Protein Kinases