REGULATION OF PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 IN CULTURED SMOOTH-MUSCLE CELLS BY INTERLEUKIN-1-ALPHA AND TUMOR-NECROSIS-FACTOR-ALPHA

Objective: Studies on the regulation of the fibrinolytic system of smooth muscle cells (SMC) are of importance for our understanding of the formation and stabilization of intravascular thrombi and the migration and proliferation of SMC during arterial injury and atheromatous plaque development. Results: We report here the stimulation of plasminogen activator inhibitor type-one (PAI-1) synthesis in cultured human mammary artery smooth muscle cells (HMASMC) by the macrophage inflammatory cytokines, interleukin 1 alpha (IL-1 alpha) and tumour necrosis factor-alpha (TNF-alpha), SMC responded to IL-1 alpha and TNF-alpha treatment with a time- and dose-dependent increase in PAI-1 protein of up to 1.9- and 4.2-fold, respectively, as determined by ELISA. Maximum cytokine effects were achieved at 14 pM IL-1 alpha and 10 nM TNF-alpha. Analysis of mRNA showed that 3.4kb and 2.4kb PAI-1 mRNA transcripts increased maximally by over 5- and 3-fold, respectively, after TNF-alpha treatment and by over 3- and 2-fold, respectively, after IL-1 alpha treatment, compared to respective, untreated controls, IL-1 alpha and TNF-alpha did not affect urokinase-type plasminogen activator (u-PA) synthesis while IL-1 alpha decreased tissue-type plasminogen activator (t-PA) in conditioned medium. Conclusion: These results suggest that the fibrinolytic potential of SMC can be regulated by IL-1 alpha and TNF-alpha which may be released by activated monocytes/macrophages, endothelial cells or SMC themselves during the development of atherosclerosis, vasculitis or vascular injury, Increased PAI-1 would suggest an antifibrinolytic tendency in the SMC microenviromnent in response to IL-1 alpha and/or TNF-alpha exposure.