INDUCTION OF APOPTOSIS BY APO-2 LIGAND, A NEW MEMBER OF THE TUMOR-NECROSIS-FACTOR CYTOKINE FAMILY

Cytokines in the tumor necrosis factor (TNF) family regulate developme nt and function of the immune system. We have isolated a new member of this family, designated Apo-2 ligand (Apo-2L), via an expressed seque nce tag. Apo-2L is a 281-amino acid protein, related most closely to F as/Apo-1 ligand. Transfected Apo-2L is expressed at the cell surface w ith its C terminus exposed, indicating a type II transmembrane protein topology. Like Fas/Apo-1 ligand and TNF, the C-terminal extracellular region of Apo-2L (amino acids 114-281) exhibits a homotrimeric subuni t structure. Soluble Apo-2L induces extensive apoptosis in lymphoid as well as non-lymphoid tumor cell lines. The effect of Apo-2L is not in hibited by soluble Fas/Apo-1 and TNF receptors; moreover, expression o f human Fas/Apo-1 in mouse fibroblasts, which confers sensitivity to i nduction of apoptosis by agonistic anti-Fas/Apo-1 antibody, does not c onfer sensitivity to Apo-2L. Hence, Apo-2L acts via a receptor which i s distinct from Fas/Apo-1 and TNF receptors. These results suggest tha t, along with other family members such as Fas/Apo-1 ligand and TNF, A po-2L may serve as an extracellular signal that triggers programmed ce ll death.