Modulation of monocyte function by activated protein C, a natural anticoagulant.
Activated protein C is the first effective biological therapy for the treatment of severe sepsis. Although activated protein C is well established as a physiological anticoagulant, emerging data suggest that it also exerts anti-inflammatory and antiapoptotic effects. In this study, we investigated the ability of activated protein C to modulate monocyte apoptosis, inflammation, phagocytosis, and adhesion. Using the immortalized human monocytic cell line THP-1, we demonstrated that activated protein C inhibited camptothecin-induced apoptosis in a dose-dependent manner. The antiapoptotic effect of activated protein C requires its serine protease domain and is dependent on the endothelial cell protein C receptor and protease-activated receptor-1. In primary blood monocytes from healthy individuals, activated protein C inhibited spontaneous apoptosis. With respect to inflammation, activated protein C inhibited the production of TNF, IL-1beta, IL-6, and IL-8 by LPS-stimulated THP-1 cells. Activated protein C did not influence the phagocytic internalization of Gram-negative and Gram-positive bioparticles by THP-1 cells or by primary blood monocytes. Activated protein C also did not affect the expression of adhesion molecules by LPS-stimulated blood monocytes nor the ability of monocytes to adhere to LPS-stimulated endothelial cells. We hypothesize that the protective effect of activated protein C in sepsis reflects, in part, its ability to prolong monocyte survival in a manner that selectively inhibits inflammatory cytokine production while maintaining phagocytosis and adherence capabilities, thereby promoting antimicrobial properties while limiting tissue damage.
Stephenson
Daniel A
DA
Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada.
Toltl
Lisa J
LJ
Beaudin
Suzanne
S
Liaw
Patricia C
PC
D000328:Adult; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D001777:Blood Coagulation / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D010587:Phagocytosis / Q000276:immunology; D011486:Protein C / Q000378:metabolism / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011486:Protein C