Release of plasminogen activator inhibitor-1 from human astrocytes is regulated by intracellular ceramide

The present study underscores a regulatory role of intracellular ceramide i n astrocytes for the release of an extracellular serine protease, tissue-ty pe plasminogen activator (t-PA), and its inhibitor, plasminogen activator i nhibitor-1 (PAI-I). Treatment of cultured human astrocytes with N-acetylsph ingosine, a cell-permeable short-chain ceramide analogue or daunorubicin th at could increase intracellular ceramide via activation of ceramide synthas e or sphingomyelin hydrolysis increased the release of t-PA and conversely decreased the PAI-1 release. Interestingly, treatment of the astrocytes wit h tumor necrosis factor (TNF)-alpha also increased the intracellular cerami de levels but caused the elevation of PAI-1 release without altering the t- PA release, These data suggest that the generation of ceramide in astrocyte s is linked at least with the regulation of PAI-I release, We also demonstr ate that the suppression of PAI-1 release with daunorubicin accelerates the cell death of neuronally differentiated PC12 cells and suggest an antiapop totic role of PAI-1 in the nervous system. (C) 2000 Wiley-Liss, Inc.