A novel tumor necrosis factor (TNF) family member has been cloned and characterized. This protein, designated TNF-related apoptosis-inducing ligand (TRAIL), consists of 281 and 291 aa in the human and murine forms, respectively, which share 65% aa identity. TRAIL is a type II membrane protein, whose C-terminal extracellular domain shows clear homology to other TNF family members. TRAIL transcripts are detected in a variety of human tissues, most predominantly in spleen, lung, and prostate. The TRAIL gene is located on chromosome 3 at position 3q26, which is not close to any other known TNF ligand family members. Both full-length cell surface expressed TRAIL and picomolar concentrations of soluble TRAIL rapidly induce apoptosis in a wide variety of transformed cell lines of diverse origin.

TWEAK is a member of the TNF ligand family that induces angiogenesis in vivo. We report cloning of a receptor for TWEAK (TweakR) from a human umbilical vein endothelial cell (HUVEC) library. The mature form of TweakR has only one hundred and two amino acids and six cysteine residues in its extracellular region. Five different assays demonstrate TWEAK-TweakR binding, and the interaction affinity constant (Kd) is within a physiologically relevant range of 2.3 +/- 0.1 nM. The TweakR cytoplasmic domain binds TRAFs 1, 2, and 3. Cross-linking of TweakR induces HUVEC growth, and mRNA levels are upregulated in vitro by a variety of agents and in vivo following arterial injury. Soluble TweakR inhibits endothelial cell migration in vitro and corneal angiogenesis in vivo.

TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a molecule that displays potent antitumor activity against selected targets. The results presented here demonstrate that human monocytes rapidly express TRAIL, but not Fas ligand or TNF, after activation with interferon (IFN)-γ or -α and acquire the ability to kill tumor cells. Monocyte-mediated tumor cell apoptosis was TRAIL specific, as it could be inhibited with soluble TRAIL receptor. Moreover, IFN stimulation caused a concomitant loss of TRAIL receptor 2 expression, which coincides with monocyte acquisition of resistance to TRAIL-mediated apoptosis. These results define a novel mechanism of monocyte-induced cell cytotoxicity that requires TRAIL, and suggest that TRAIL is a key effector molecule in antitumor activity in vivo.

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