Role of oxidative damage and IL-1β-converting enzyme-like proteases in Fas-based cytotoxicity exerted by effector T cells

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Abstract
The Implication of oxidative damage and/or intact mitochondrial function in physiological Fas-based cytotoxicity has been tested using the cytolytic hybridoma d11S and the CD8+ CTL clone KB5.C20, previously stimulated to express Fas ligand (FasL) on their surface, as effectors and U937 or U937-p° cells (depleted of mitochondrial DNA) as targets. Immobilized anti-Fas mAb, which induced death of U937 cells, Inhibited the growth of U937-p° cells but without inducing cell death. By contrast, FasL-expressing effectors readily killed both targets, with induction of DNA fragmentation, in 20 h assays. These results demonstrate the lack of involvement of mitochondrial-derived free radicals and/or Intact mitochondrial function in physiological Fas-based cytotoxicity. Supplementation of Fas-sensitive cells (Jurkat, U937, L1210Fas) with a polyunsaturated fatty acid, which induces cell death through the generation of lipid free radicals, resulted in the potentiation of Fas-based cytotoxicity. This potentiating effect, but not Fas-based cytotoxicity Itself, was eliminated by the physiological antioxidant vitamin E. On the other hand, the IL-1β-converting enzyme (ICE)-like protease tetrapeptide inhibitor Ac-YVAD-cmk partially Inhibited Fas-based cytotoxicity, while the specific inhibitor of CPP32/Yama Ac-DEVD-CHO was a much more effective inhibitor of Fas-Induced apoptosis. It was concluded that Fas-Induced cytotoxicity was clearly dependent on ICE-LIke protease activation, and especially on that of CPP32 in Fas-sensitive cells, including mitochondrial DNA-depleted ones.

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