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Prepublished online as a Blood First Edition Paper on March 6, 2003; DOI 10.1182/blood-2002-11-3559.
Submitted November 25, 2002
Accepted February 24, 2003
Vitamin C inhibits FAS-induced apoptosis in monocytes and U937 cells
Isabel Perez-Cruz, Juan M Carcamo, and David W Golde*
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
* Corresponding author; email: d-golde{at}ski.mskcc.org.
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 pro-apoptotic 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 pharmacological 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 its 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.
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