RETINOIC ACID POTENTIATES PHORBOL ESTER-MEDIATED INDUCTION OF UROKINASE AND PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-2 IN HUMAN MYELOID LEUKEMIC-CELL LINES

We investigated the interactive regulation of the plasminogen activato rs (PAs) and their inhibitors (PAIs) by all-trans-retinoic acid (RA) i n the presence and absence of the phorbol ester, phorbol myristate ace tate (PMA), in four developmentally distinct human myeloid leukemic ce ll lines. Treatment of HL-60, K562, THP-1, and U937 cells with PMA res ulted in an induction of urokinase-type PA (u-PA), the u-PA receptor ( u-PAR), and PAI types 1 and 2 (PAI-1 and PAI-2). The addition of RA al one failed to alter gene expression or antigen production of PAI-1, PA I-2, or u-PAR. However, RA potentiated PMA-mediated induction of PAI-2 mRNA in HL-60 and U937 cells and PAI-2 antigen in all four cell lines . The effect of PMA on u-PA mRNA was also potentiated by RA in HL-60 a nd U937 cells. A similar, but transient, effect was seen on u-PA antig en levels. Run-on transcription analysis confirmed that these effects were due at least in part to changes in gene template activity. Furthe rmore, RA did not potentiate the effects of PMA on either u-PAR or PAI -1. In fact, in U937 cells, RA inhibited PMA-induced PAI-1 antigen sec retion by approximately 60%. It would seem that interactive regulation of these genes allows for greater diversity of control, which may, in turn, be required for localized control of plasminogen-dependent extr acellular proteolysis generated by monocytes/macrophage during cell mi gration and tissue remodeling.