Astrocytes are major glial cells in central nervous system (CNS) and are known to express death receptors or ligands that can induce apoptosis of astrocytes or other brain cells. We have previously confirmed that cultured human astrocytes express fas and fas ligand and their expression may be regulated by various cytokines found in CNS. Because fas can rnediate cell death known as apoptosis, we investigated fas-mediated cell death in cultured human astrocytes and evaluated factors that may influence the fas-mediated apoptosis in astrocytes. Pretreatment of interferon-r and TNF-a increased cell death in astrocytes. Cell death induced by fas ligation was confirmed as apoptosis by phosphatidylserine translocation in cell membrane. Cycloheximide, protein synthesis inhibitor, potentiated fas-mediated cell death. However, buthionine sulfoxine did not potentiate fas-mediated apoptosis. Dexamethasone blocked cell death in dose-dependent and time-dependent manners. These findings collectively show that fas expressed on cultured human fetal astrocytes can induce apoptotic cell death after pretreatment of interferon-r and/or TNF-a. Therefore, the fas-fas ligand system in CNS may regulate the glial degeneration and may participate the neuronal loss in certain conditions. Furthermore, fas-mediated apoptosis of astrocytes can be potentiated by protein synthesis inhibitors and can be blocked by dexamethasone.