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From the Laboratory of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, B-9000 Ghent, Belgium

Murine L929 fibrosarcoma cells treated with tumor necrosis factor (TNF) rapidly die in a necrotic way, due to excessive formation of reactive oxygen intermediates. We investigated the role of caspases in the necrotic cell death pathway. When the cytokine response modifier A (CrmA), a serpin-like caspase inhibitor of viral origin, was stably overexpressed in L929 cells, the latter became 1,000-fold more sensitive to TNF-mediated cell death. In addition, TNF sensitization was also observed when the cells were pretreated with Ac-YVAD-cmk or zDEVD-fmk, which inhibits caspase-1– and caspase-3–like proteases, respectively. zVAD-fmk and zD-fmk, two broad-spectrum inhibitors of caspases, also rendered the cells more sensitive, since the half-maximal dose for TNF-mediated necrosis decreased by a factor of 1,000. The presence of zVAD-fmk also resulted in a more rapid increase of TNF-mediated production of oxygen radicals. zVAD-fmk–dependent sensitization of TNF cytotoxicity could be completely inhibited by the oxygen radical scavenger butylated hydroxyanisole. These results indicate an involvement of caspases in protection against TNF-induced formation of oxygen radicals and necrosis.

Research was supported by the Interuniversitaire Attractiepolen and the Fonds voor Geneeskundig Wetenschappelijk Onderzoek, as well as by a European Community Biomed Program grant BMH4-CT96-0300. R. Beyaert is a postdoctoral researcher, G. Denecker a research assistant, and P. Vandenabeele a postdoctoral researcher with the Fonds voor Wetenschappelijk Onderzoek–Vlaanderen. G. Van Loo is a fellow with the Vlaams Instituut voor de Bevordering van het Wetenschappelijk-technologisch Onderzoek in de Industrie.

Abbreviations used: BHA, butylated hydroxyanisole; CrmA, cytokine response modifier A; DD, death domain; DEM, diethylmaleate; DHR123, dihydrorhodamine 123; NF, nuclear factor; PI, propidium iodide; tBuOOH, tert-butyl hydroperoxide.

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