An oxidative mechanism of interferon induced priming of the Fas pathway in Fanconi anemia cells.
Hematopoietic progenitor cells from children with Fanconi anemia of the C complementation group (FA-C) are excessively apoptotic and hypersensitive to various extracellular cues including Fas-ligand, tumor necrosis factor-alpha and double-stranded RNA. Interferon (IFN)-gamma is known to augment apoptotic responses of these factors. The "priming" effect of IFN-gamma is not fully explained. In view of the strong evidence that FA cells are intolerant of oxidative stress, we tested the notion that IFN-priming involves the induction of reactive oxygen species (ROS) in two FA-C B-lymphocyte cell lines and in peripheral blood neutrophils and mononuclear cells of FA patients. We also investigated whether the combination of IFN-gamma and Fas created an intracellular environment that promoted apoptosis. Significantly lower doses of IFN-gamma induced ROS accumulation in neutrophils and mononuclear cell of FA patients compared to cells of normal individuals. Enhanced ROS accumulation and decreased intracellular glutathione levels were observed in FA-C B-cell lines primed with IFN-gamma and treated with agonistic anti-Fas antibody than in isogenic control cells corrected with FANCC. The above treatment also induced caspase-3 and -8 activation as well as apoptosis. That antioxidants reduced the priming effect of IFN-gamma in Fas and IFN-gamma-treated FA lymphoblast cells, demonstrates that ROS represent a critical effector mechanism for the exaggerated responses to IFN-gamma characteristic of FA-C cells.[1]References
- An oxidative mechanism of interferon induced priming of the Fas pathway in Fanconi anemia cells. Pearl-Yafe, M., Halperin, D., Halevy, A., Kalir, H., Bielorai, B., Fabian, I. Biochem. Pharmacol. (2003) [Pubmed]
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