INTERLEUKIN-1-BETA UP-REGULATES THE PLASMINOGEN-ACTIVATOR PLASMIN SYSTEM IN HUMAN MESANGIAL CELLS

The plasminogen activators (PA), which are regulated by their specific inhibitor, PAI-1, convert the zymogen plasminogen to plasmin, a prote ase involved in fibrinolysis and extracellular matrix turnover. Interl eukin 1 beta (IL-1) is a key cytokine released from infiltrating monoc ytes/macrophages during the initial stages of glomerular injury. We in vestigated the effects of IL-1 on the production of tissue-type plasmi nogen activator (t-PA), urokinase (u-PA) and PAI-1 by glomerular cells . IL-1 significantly increased the synthesis of t-PA by mesangial cell s and glomerular epithelial cells (P < 0.005 for both cell types), whi le u-PA production was unaltered. PAI-1 in mesangial cell supernatants was significantly lower when cultured in the presence of IL-1 (P < 0. 008), and the synthesis decreased in a time and dose dependent manner. The effects of IL-1 were elimininated by anti-IL-1 neutralizing antib odies. The PAI-1 sequestered in the extracellular matrix of mesangial cells was also decreased. No significant change in PAI-1 synthesis by epithelial cells was observed with exogenous IL-1. Northern blot analy sis paralleled the protein results, demonstrating an increase in t-PA and a decrease in PAI-1 mRNA of mesangial cells after 6 and 24 hours s timulation with 10 U/ml IL-1. These studies suggest a role for IL-1 in regulating localized proteolysis by mesangial cells during acute infl ammation.