Regulation of plasminogen activator inhibitor type 1 in cultured smooth muscle cells by interleukin 1α and tumour necrosis factor-α

Summary

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 1α (IL-1α) and tumour necrosis factor-α (TNF-α). SMC responded to IL-1α and TNF-α 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-1α and 10 nM TNF-α. Analysis of mRNA showed that 3.4 kb and 2.4 kb PAI-1 mRNA transcripts increased maximally by over 5- and 3-fold, respectively, after TNF-α treatment and by over 3- and 2-fold, respectively, after IL-1α treatment, compared to respective, untreated controls. IL-1α and TNF-α did not affect urokinase-type plasminogen activator (u-PA) synthesis while IL-1α 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-1α and TNF-α 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 microenvironment in response to IL-1α and/or TNF-α exposure.