Vitamin C inhibits FAS-induced apoptosis in monocytes and U937 cells.
The FAS receptor-FAS ligand system is a key apoptotic pathway for cells of the immune system. Ligation of the FAS-receptor (CD95) induces apoptosis by activation of pro-caspase-8 followed by downstream events, including an increase in reactive oxygen species (ROS) and the release of proapoptotic factors from the mitochondria, leading to caspase-3 activation. We investigated the role of vitamin C in FAS-mediated apoptosis and found that intracellular accumulation of pharmacologic concentrations of vitamin C inhibited FAS-induced apoptosis in the monocytic U937 cell line and in fresh human monocytes. Cells were loaded with vitamin C by exposure to dehydroascorbic acid (DHA), thereby circumventing in vitro artifacts associated with the poor transport and pro-oxidant effects of ascorbic acid (AA). Vitamin C inhibition of FAS-mediated apoptosis was associated with reduced activity of caspase-3, -8, and -10, as well as diminished levels of ROS and preservation of mitochondrial membrane integrity. Mechanistic studies indicated that the major effect of vitamin C was inhibition of the activation of caspase-8 with no effect on it enzymatic activity. An independent action of high intracellular concentrations of vitamin C on mitochondrial membrane stabilization was also detected. These studies illuminate the nature of redox-dependent signaling in FAS-induced apoptosis of human monocytes and suggest that vitamin C can modulate the immune system by inhibiting FAS-induced monocyte death.
Perez-Cruz
Isabel
I
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Carcamo
Juan M
JM
Golde
David W
DW
D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D003683:Dehydroascorbic Acid; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008928:Mitochondria / Q000648:ultrastructure; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000032:analysis; D020298:U937 Cells; D019014:fas Receptor / Q000502:physiology*
D017382:Reactive Oxygen Species; D019014:fas Receptor; D020169:Caspases; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid