Different apoptotic pathways mediated by Fas and the tumor-necrosis-factor receptor. Cytosolic phospholipase A2 is not involved in Fas-mediated apoptosis.

Fas is a cell-surface receptor that belongs to the tumor-necrosis factor (TNF)/nerve growth factor receptor family. Fas can transduce an apoptotic signal through the death domain in the cytoplasmic region, which has similarity with the corresponding region of the TNF type-I receptor. Here, we expressed human Fas in mouse L929 cells or its subline (C12), which express extremely low levels of cytosolic phospholipase A2 (cPLA2). L929 cells were sensitive to the cytotoxic activity of TNF, while C12 cells were resistant. Cross-linking of human Fas with anti-(human Fas antibody) Ig killed both L929 transformants and C12 transformants expressing human Fas. Various inhibitors of the arachidonate metabolism significantly inhibited the TNF-induced cytotoxicity in L929 cells, but they did not have any effect on Fas-mediated apoptosis. These results indicated that cPLA2 is required for TNF-induced apoptosis, whereas it is dispensable for Fas-mediated apoptosis, and suggested that the TNF receptor and Fas use different signaling pathways for apoptosis.