REGULATION OF THE UPAR UPA SYSTEM EXPRESSED ON MONOCYTES BY THE DEACTIVATING CYTOKINES, IL-4, IL-10 AND IL-13 - CONSEQUENCES ON CELL-ADHESION TO VITRONECTIN AND FIBRINOGEN/

Urokinase (uPA) and its receptor (uPAR) have been proposed to be invol ved in monocyte migration by inducing degradation of matrix proteins, In addition, uPAR is also implicated in cell adhesion to the vascular wall, The adhesive function of uPAR depends on a direct interaction wi th vitronectin which is increased by uPA and by modification of cell s urface integrin (such as CD11b-CD18) when associated to uPAR. In this study we analysed the role of three deactivating cytokines, IL-4, IL-1 0 and IL-13, on the surface expression of uPA, uPAR and CD11b by monoc ytes and their consequences on monocyte adhesion to immobilized fibrin ogen and vitronectin. IL-10 induced a decrease in uPA and CD11b after 18 h incubation and a delayed decrease in uPAR which was only signific ant after 48 h incubation. These results may explain the decrease in m onocyte adhesion, which was observed after an 18 h incubation with IL- 10, on immobilized vitronectin and fibrinogen. In contrast, IL-4 and I L-13 induced a decrease in uPAR after 18 h and a significant increase in uPA both in the cell lysates and at the cell surface, as well as an increase in cell surface associated CD11b. These cytokines did not mo dify cell adhesiveness to vitronectin or fibrinogen despite the increa se in CD11b-CD18. This could be due to the decrease in uPAR because CD 11b-CD18/uPAR forms a cell-adhesion complex. In addition, the increase in uPA induced by IL-4 could counterbalance the direct interaction of uPAR with vitronectin. The increase in uPA suggests that IL-4 and IL- 13 could induce plaque fissuring by monocytes, whereas IL-10 may induc e protection against matrix protein degradation by decreasing uPA.