Retinoic acid stimulates plasminogen activator inhibitor 2 production by blood mononuclear cells and inhibits urokinase‐induced extracellular proteolysis

• Published in: British journal of haematology Vol. 107; no. 2; pp. 294 - 299
• Main Authors: Montemurro, P., Barbuti, G., Conese, M., Gabriele, S., Petio, M., Colucci, M., Semeraro, N.
• Format: Journal Article
• Language: English
• Published: Oxford, U.K. and Cambridge, USA Blackwell Science Ltd 01.11.1999; Blackwell; Blackwell Publishing Ltd
• Subjects: all‐trans‐retinoic acid; Biological and medical sciences; blood mononuclear cells; Blotting, Northern; Cell physiology; Effects of physical and chemical agents; fibrinolysis; Fibrinolysis - drug effects; Fibrinolysis - physiology; Fundamental and applied biological sciences. Psychology; Hematology; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Molecular and cellular biology; plasminogen activator inhibitor 2; Plasminogen Activator Inhibitor 2 - biosynthesis; Time Factors; Tretinoin - pharmacology; Urokinase-Type Plasminogen Activator - biosynthesis; urokinase‐type plasminogen activator; Human; u-Plasminogen activator; Serine endopeptidases; Monocyte; Enzyme; Leukocyte; Retinoid; Biosynthesis; Extracellular; Fibrinolysis; In vitro; Peptidases; Plasminogen activator inhibitor 2; Mononuclear cell; Proteolysis; Hydrolases; Retinoic acid; Tretinoin
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.1999.01698.x

Retinoids have been shown to modulate several functions of mononuclear phagocytes. We investigated the in vitro effect of all‐trans‐retinoic acid (ATRA) on the production of two major fibrinolytic components, urokinase‐type plasminogen activator (u‐PA) and PA inhibitor 2 (PAI‐2), by human blood mononuclear cells (MNC). ATRA caused a dose‐dependent (range 0.01–10 μm) accumulation of PAI‐2 antigen and activity into the cell culture medium, with a maximal increase (about 5‐fold over control) at a concentration of 1–10 μm. Similarly, a dose‐dependent increase in PAI‐2 antigen was observed in cell extracts upon ATRA stimulation. Northern blot analysis showed a parallel increase in the amount of PAI‐2 mRNA in ATRA‐treated cells. Time‐course experiments with 1 μm ATRA showed enhanced PAI‐2 mRNA expression as early as 2 h, reaching a maximum at 4–6 h and then declining at 18–24 h, and a time‐dependent increase in PAI‐2 antigen in the cell culture medium. At variance with PAI‐2, u‐PA was not influenced by the drug. To establish whether ATRA‐induced changes influenced the fibrinolytic process, we evaluated the effect of MNC stimulated with ATRA on u‐PA‐induced degradation of diluted plasma clots. ATRA‐treated cells markedly inhibited clot lysis induced by low concentrations of u‐PA. The effect was due to enhanced extracellular PAI‐2 accumulation since it was observed with conditioned medium from ATRA‐treated cells; it was abolished by the addition of neutralizing anti‐PAI‐2 antibodies and was negligible when single‐chain t‐PA was used instead of u‐PA. Since monocyte/macrophage‐mediated, plasminogen‐dependent extracellular proteolysis has been proposed as an important mechanism of tissue damage in several inflammatory states, our findings might contribute to better explain the anti‐inflammatory properties of retinoids.