QUALITATIVE AND QUANTITATIVE DIFFERENCES IN THE CELLULAR-RESPONSES MEDIATED THROUGH FAS ANTIGEN AND TUMOR-NECROSIS-FACTOR RECEPTOR

Like tumor necrosis factor (TNF), antibodies against the Fas antigen ( anti-Fas) are cytotoxic to some and induce proliferation of other Fas- expressing cells, In this study, we compared cellular responses mediat ed through TNF with anti-Fas using a T cell line (Jurkat) and a macrop hage cell line (U-937), These two cell types differed in that the Jurk at cells expressed higher levels of Fas antigen than U-937 cells, wher eas the latter expressed higher levels of the p80 form of the TNF rece ptor than Jurkat cells, Treatment for 72 h with anti-Fas inhibited the growth of both Jurkat and U-937 cells, the 50% inhibitory concentrati ons (IC50) being 10 and 100 ng/ml, respectively, Under similar conditi ons, the IC50 for TNF was >100 and 0.8 ng/ml for Jurkat and U-937 cell s, respectively, Like TNF, the cytotoxic effects of anti-Fas were pote ntiated by cycloheximide, showing they did not require protein synthes is, Interestingly, in the presence of cycloheximide, the kinetics of c ell killing was more rapid for TNF than anti-Fas (50% inhibition occur red at 3 versus 6 h), Treatment of both cell types with anti-Fas led t o time-dependent DNA fragmentation, but TNF-induced DNA fragmentation occurred only in the presence of cycloheximide, Pretreatment of cells with TNF led to resistance to TNF but not to anti-Fas, suggesting that the receptors for the two are not cross-modulated. Furthermore, TNF a ctivated the nuclear transcriptional factor NF-kappa B in both cell ty pes, whereas anti-Fas had no effect, Overall, our results demonstrate that anti-Fas and TNF transduce overlapping and nonoverlapping signals in macrophage-like and T cell lines through distinct pathways.