Endocrinology, Vol 133, 1724-1730, Copyright © 1993 by Endocrine Society

ARTICLES

Retinoic acid potentiates phorbol ester-mediated induction of urokinase and plasminogen activator inhibitor type 2 in human myeloid leukemic cell lines

WA Schuster, RL Medcalf and EK Kruithof
Hematology Division, University Hospital, Lausanne, Switzerland.

We investigated the interactive regulation of the plasminogen activators (PAs) and their inhibitors (PAIs) by all-trans-retinoic acid (RA) in the presence and absence of the phorbol ester, phorbol myristate acetate (PMA), in four developmentally distinct human myeloid leukemic cell lines. Treatment of HL-60, K562, THP-1, and U937 cells with PMA resulted 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 alone failed to alter gene expression or antigen production of PAI-1, PAI-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 and U937 cells. A similar, but transient, effect was seen on u- PA antigen levels. Run-on transcription analysis confirmed that these effects were due at least in part to changes in gene template activity. Furthermore, 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 secretion 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 extracellular proteolysis generated by monocytes/macrophage during cell migration and tissue remodeling.