U937 cells can utilize plasminogen activator to regulate human interferon-gamma

Urokinase-type plasminogen activator (uPA) converts the proenzyme plasminogen to plasmin and thereby contributes to processes like cell migration, tissue remodeling, and cytokine processing. We report here that uPA produced by the human U937 promonocytic cell line also initiated the inactivation of recombinant interferon-gamma (rIFN-gamma) by plasmin-mediated proteolysis. When cultured serum-free with plasminogen, U937 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 the electrophoretic mobility of rIFN-gamma on polyacrylamide gels, consistent with limited proteolysis of the lymphokine. Culturing U937 cells or blood monocytes for 48 h led to an elevated expression of their surface uPA and an increase in their capacity to produce plasmin and inactivate rIFN-gamma. The ability of rIFN-gamma to induce Fc receptors on U937 cells could also be prevented by providing the cells with a source of exogenous plasminogen, indicating that U937 cells could control their own activation in vitro through the action of uPA. The results of these studies support the conclusion that mononuclear phagocytes have the capacity to use uPA to regulate cytokine activity in vitro.