GANGLIOSIDES PROTECT FROM TNF-ALPHA-INDUCED APOPTOSIS

The modulation of tumor necrosis factor alpha-mediated cytotoxicity by gangliosides was analyzed. When cells of the TNFalpha-sensitive fibro sarcoma cell line L929 were incubated for 16 h with recombinant TNFalp ha (156 or 312 pg/ml), they were lysed to 65.2% or 78.0%, respectively . The presence of a bovine brain ganglioside mixture (BBG, Cronassial) inhibited the TNFalpha-mediated lysis in a dose-dependent manner (IC5 0 almost-equal-to 1 mg/ml). Maximum inhibition was achieved with 2 mg/ ml BBG (82.6% inhibition for 156 pg/ml TNFalpha and 88.5% inhibition f or 312 pg/ml TNFalpha). In situ nick translation revealed that BBG (2 mg/ml) significantly reduces the number of cells with TNFalpha-induced DNA-strand breaks from 71.2% to 6.6% (P<0.0001), indicating a protect ion against TNFalpha-mediated apoptosis. We conclude that BBG prevents the cytotoxic action of TNFalpha on tumor cells. The inhibitory effec t may be due to an interference of gangliosides with intracellular sig nal transduction pathways, resulting in an inhibition of the activatio n of DNA-cleaving endonucleases.