Release of plasminogen activator inhibitor-1 from human astrocytes is regulated by intracellular ceramide.
The present study underscores a regulatory role of intracellular ceramide in astrocytes for the release of an extracellular serine protease, tissue-type plasminogen activator (t-PA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1). Treatment of cultured human astrocytes with N-acetylsphingosine, a cell-permeable short-chain ceramide analogue or daunorubicin that could increase intracellular ceramide via activation of ceramide synthase or sphingomyelin hydrolysis increased the release of t-PA and conversely decreased the PAI-1 release. Interestingly, treatment of the astrocytes with tumor necrosis factor (TNF)-alpha also increased the intracellular ceramide levels but caused the elevation of PAI-1 release without altering the t-PA release. These data suggest that the generation of ceramide in astrocytes is linked at least with the regulation of PAI-1 release. We also demonstrate that the suppression of PAI-1 release with daunorubicin accelerates the cell death of neuronally differentiated PC12 cells and suggest an antiapoptotic role of PAI-1 in the nervous system.
Kimura
M
M
Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
Soeda
S
S
Oda
M
M
Ochiai
T
T
Kihara
T
T
Ono
N
N
Shimeno
H
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D002518:Ceramides; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; C064769:N-acetylsphingosine; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha; D010959:Tissue Plasminogen Activator; D013110:Sphingosine; D003630:Daunorubicin