Endogenous receptor-bound urokinase mediates tissue invasion of human monocytes.
Macrophages have a marked capacity to invade tissue in the course of cellular immune reactions that is thought to be based on the action of urokinase (u-PA). u-PA is an ubiquitous serine protease that converts the zymogen plasminogen into the active protease plasmin. u-PA binds to specific receptors on the macrophage thereby enabling the cell to degrade interstitial tissue in the microenvironment. Two cytokines produced in the course of cellular immune reactions, IFN-gamma and TNF-alpha, increase the number of u-PA receptors on human cultured monocytes from 14,000 to 64,000 and 30,000 receptors/cell, respectively. We used an amnion invasion assay to investigate whether activated human monocytes exhibit an enhanced capacity to invade interstitial tissue in correlation to the increased numbers of u-PA receptors. We show in this study that IFN-gamma, which increases the number of endogenously occupied and saturable u-PA receptors, causes a threefold increase of monocyte invasion into amnion tissue in comparison to control cells. The anti-u-PA mAb MPW5UK, which blocks the activity of u-PA, inhibits monocyte invasiveness significantly. In contrast, TNF-alpha, which increases only the number of saturable u-PA receptors on monocytes, does not enhance their invasiveness. This finding suggests that only endogenously occupied u-PA receptors are instrumental in monocyte invasiveness. This conclusion is further supported by the findings that: 1) saturation of monocytes with u-PA does not further increase their invasiveness and that 2) plasminogen-activator inhibitor-2, a specific inhibitor of u-PA associated with endogenously occupied, but not of u-PA bound to saturable receptors, inhibits monocyte invasiveness completely.
Kirchheimer
J C
JC
Department of Rheumatology and Immunology, Brigham and Women's Hospital, Boston, MA 02115.
Remold
H G
HG
D000650:Amnion / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001667:Binding, Competitive; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015849:Plasminogen Inactivators / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015849:Plasminogen Inactivators; D011956:Receptors, Cell Surface; D014568:Urokinase-Type Plasminogen Activator