A decrease in intracellular glutathione concentration precedes the onset of apoptosis in murine thymocytes.
Free radical damage has been implicated in the induction of apoptosis in some cells. We investigated whether the status of a cell's oxidant defence system is involved in the signalling pathways triggering apoptosis. We used three unrelated agents, dexamethasone, thapsigargin and gliotoxin to induce apoptosis in thymocytes from 10-day-old BALB/c mice. With all stimuli there was a correlation between the percentage of cells undergoing apoptosis (as measured with propidium iodide DNA staining) and the percentage of cells with lowered [GSH]i. Treatment with either 1 mM reduced glutathione or 10 nM thapsigargin inhibited dexamethasone-induced apoptosis in thymocytes at 6 h, as well as the rise in the percentage of cells with lowered [GSH]i that normally accompanied the onset of apoptosis. Furthermore, following treatment of thymocytes with oxidized glutathione, a normal product of the action of the cell's oxidant defence system, high levels of apoptosis were observed. This suggested that the onset of apoptosis was not simply the result of a loss of GSH from the cytosol. From our evidence we suggest that a decrease in [GSH]i, or an increase in [GSSG]i or perhaps a change in the ratio of [GSH]i to [GSSG]i constitutes a trigger for apoptosis.
Beaver
J P
JP
Division of Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra/Australia.
Waring
P
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005912:Gliotoxin / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D019803:Glutathione Disulfide; D051379:Mice; D010084:Oxidation-Reduction; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D013729:Terpenes; D005912:Gliotoxin; D019284:Thapsigargin; D003907:Dexamethasone; D000252:Calcium-Transporting ATPases; D005978:Glutathione; D019803:Glutathione Disulfide