Differential regulation of tissue factor and plasminogen activator inhibitor by human mononuclear cells.
Fibrin is a hallmark of immune-mediated tissue lesions. The presence of fibrin in such lesions implies both the formation of fibrin via coagulation and the accompanying restriction of fibrinolysis, allowing fibrin to persist. Previous work has shown that human monocytes exposed to an inflammatory stimulus such as lipopolysaccharide (LPS) produce both tissue factor (TF) and plasminogen activator inhibitor--type 2 (PAI-2). These two proteins favor fibrin deposition, and evidence implies that cellular production of these two molecules may be linked. Another proinflammatory process pertinent to immune-mediated tissue damage and fibrin deposition is the response to alloantigen. Peripheral-blood mononuclear cells (PBM), consisting of lymphocytes and monocytes together, responded to alloantigen stimulation with differential expression of TF and PAI-2. PBM exposed to alloantigen developed high levels of TF activity, with no concomitant increase in PAI-2 activity or antigen. Alloantigen-stimulated PBM did not accumulate intracellular PAI-2, nor did they degrade PAI-2 added to cultures. This lack of PAI-2 production was not due to inadequate stimulation, as tritiated thymidine uptake and TF production demonstrated recognition of, and a vigorous reaction to, alloantigen. The divergent TF and PAI-2 responses of PBM exposed to alloantigen was maintained over 5 days and was reflected by mRNA profiles. These results imply that under specific physiologically relevant conditions, the procoagulant and antifibrinolytic effectors of inflammatory mononuclear cells can be independently regulated. This would imply more flexibility to monocyte mechanisms that favor fibrin deposition than previously thought.
Schwartz
B S
BS
Department of Medicine, University of Wisconsin, Madison.
Bradshaw
J D
JD
D015152:Blotting, Northern; D002478:Cells, Cultured; D006706:Homeostasis; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D007700:Kinetics; D009000:Monocytes / Q000502:physiology*; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors*; D015849:Plasminogen Inactivators / Q000032:analysis / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011863:Radioimmunoassay; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D013925:Thromboplastin; D010960:Plasminogen Activators