U937 CELLS CAN UTILIZE PLASMINOGEN-ACTIVATOR TO REGULATE HUMAN INTERFERON-GAMMA

Urokinase-type plasminogen activator (uPA) converts the proenzyme plas minogen to plasmin and thereby contributes to processes like cell migr ation, tissue remodelling, and cytokine processing. We report here tha t uPA produced by the human U937 promonocytic cell line also initiated the inactivation of recombinant interferon-gamma (rIFN-gamma) by plas min-mediated proteolysis. When cultured serum-free with plasminogen, U 937 promonocytic cells generated measurable levels of plasmin activity and destroyed the antiviral activity of exogenously added rIFN-gamma. This effect was not seen in the absence of plasminogen, was prevented by inhibitors of uPA and plasmin, and was accompanied by changes in t he electrophoretic mobility of rIFN-gamma on polyacrylamide gels, cons istent with limited proteolysis of the lymphokine. Culturing U937 cell s or blood monocytes for 48 h led to an elevated expression of their s urface uPA and an increase in their capacity to produce plasmin and in activate rIFN-gamma. The ability of rIFN-gamma to induce Fc receptors on U937 cells could also be prevented by providing the cells with a so urce of exogenous plasminogen, indicating that U937 cells could contro l their own activation in vitro through the action of uPA. The results of these studies support the conclusion that mononuclear phagocytes h ave the capacity to use uPA to regulate cytokine activity in vitro.