Segregation of APO-1/Fas antigen- and tumor necrosis factor receptor-mediated apoptosis.

The cytokine tumor necrosis factor (TNF) and the APO-1/Fas ligand represent typical inducers of apoptosis, i.e. programmed cell death. A limited sequence homology between the TNF receptor TR60 (p55) and the APO-1/Fas (CD95) antigen in their intracellular domains suggests overlapping signaling pathways. The TNF-sensitive cell line KYM-1, which expresses high numbers of both TNF receptors and the APO-1/Fas antigen, is highly sensitive towards triggering of apoptosis by each of the TNF receptors, but resistant to APO-1/Fas stimulation. The opposite response pattern was obtained using the B lymphoid line SKW 6.4, which also co-expresses all three cell surface molecules. Furthermore, no co-modulation of APO-1/Fas by down-regulation of cell surface expressed TR60 and/or TR80 receptors, and vice versa, was found. These data argue against a physical interaction of TNF receptors with APO-1/Fas and, in addition, demonstrate cell specific control of induction of apoptosis and usage of distinct signaling pathways by these receptor molecules.