Microglial tissue plasminogen activator (tPA) triggers neuronal apoptosis in vitro.
Several CNS disorders feature microglial activation. Microglia are known to have both restorative and cytotoxic capabilities. Neuronal apoptosis has been noted after an acute insult such as ischemia. Microglia may participate in this event. We previously showed that conditioned medium (CM) harvested from peritoneal macrophages or from activated microglia triggered apoptosis in rat hippocampal neurons in culture. We wished to characterize the factor responsible for triggering neuronal death. Quiescent microglia produced CM that did not disrupt hippocampal neurons. Lipopolysaccharide-activated microglia produced CM which resulted in neuronal death. This effect was blocked by plasminogen activator inhibitor-1, by tPA STOP, and by co-incubation with tPA antibody. Recombinant human tPA exaggerated the neurotoxic effects of microglial CM, while tPA alone was toxic only at very high concentrations. This in vitro system, which probably excludes any significant impact of microglial free radicals, suggests that microglial tPA may contribute significantly to hippocampal neuronal death.
Flavin
M P
MP
Department of Pediatrics, Queen's University, Kingston, Ontario, Canada. mf6@post.queensu.ca
Zhao
G
G
Ho
L T
LT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000737:chemistry* / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D011233:Precipitin Tests; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000276:immunology / Q000494:pharmacology*
D017077:Culture Media, Conditioned; D008070:Lipopolysaccharides; C491894:MAP6 protein, human; C113727:Map6 protein, rat; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D017395:Plasminogen Activator Inhibitor 1; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; D010959:Tissue Plasminogen Activator