Matrix-bound plasminogen activator inhibitor type 1 inhibits the invasion of human monocytes into interstitial tissue.
Invasion of tissue by monocytes in the course of cellular immune reactions is a multistep process that is thought to be based on the action of urokinase type plasminogen activator (u-PA), an ubiquitous serine protease able to convert the zymogen plasminogen into the active protease plasmin. Expression and occupation of urokinase-type plasminogen activator receptors (u-PA-R) are known to be up-regulated by IFN-gamma and TNF-alpha, and endogenously occupied u-PA-R were found to be instrumental in monocyte invasiveness. We used the amnion invasion assay to investigate whether monocyte invasiveness is affected by matrix-bound plasminogen activator inhibitors (PAI) and by fluid phase u-PA. We show in this study that preincubation of amnion membranes with 1.5 U/cm2 PAI-1 decreases invasion of IFN-gamma activated monocytes by 70% compared with controls. Anti-vitronectin antibodies, which block PAI-1 binding to the matrix, abrogate the inhibitory effect of PAI-1 on monocyte invasiveness, indicating that active PAI-1 is bound via matrix-associated vitronectin. In contrast, preincubation of the amnion membrane with PAI-2 which does not bind to the extracellular matrix has no effect on monocyte invasiveness. Finally, the inhibitory action of matrix-bound PAI-1 can be abrogated by addition of 5 IU/ml u-PA to the monocytes in the invasion chamber. These findings indicate that monocyte invasiveness might be regulated not only by expression and occupation of u-PA-R but also by matrix-bound PAI-1.
Department of Orthopedics, University of Vienna, Austria.
J C
JC
Kirchheimer
B R
BR
Binder
H G
HG
Remold
D000650:Amnion; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D009000:Monocytes / Q000166:cytology*; D015849:Plasminogen Inactivators / Q000494:pharmacology*; D011485:Protein Binding; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D019096:Vitronectin
D006023:Glycoproteins; D015849:Plasminogen Inactivators; D019096:Vitronectin; D014568:Urokinase-Type Plasminogen Activator