Involvement of caspase 8 and c-FLIP_L in the proangiogenic effects of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine of the tumour necrosis factor superfamily, is a potent cell-apoptosis inducer, although its effects vary as a function of concentration. In fact, low concentrations of TRAIL are associated with non-apoptotic effects, such as cell proliferation. Here, the effects of TRAIL at different concentrations have been evaluated on mitogenesis and migration on human umbilical vein endothelial cells (HUVEC) in vitro, as well as in the chick embryo chorioallantoic membrane (CAM) angiogenesis model in vivo. At low concentrations, TRAIL promoted either mitogenesis or migration of HUVEC, evaluated using the wound healing method. Cleavage of caspase 8 was evaluated along with expression of the caspase 8-like molecule, cellular FLICE-inhibitory protein (long form) (c-FLIP_L). Low concentrations of TRAIL failed to induce caspase 8 processing, whereas high concentrations induced apoptosis of HUVEC and activation of caspase 8. Moreover, TRAIL induced a significant angiogenic response in the CAM assay in vivo, comparable with that of vascular endothelial growth factor. These data suggest that the non-apoptotic effects of TRAIL include mitogenesis and increased mobility of endothelial cells, and eventually angiogenesis. In addition, the results demonstrate that the c-FLIP_L level is also modulated by differences in TRAIL concentration, suggesting its involvement in the divergent effects of TRAIL. In conclusion, this study envisions a proangiogenic role of TRAIL, suggesting that TRAIL may represent a target for pharmacological manipulation. The apoptosis inducer TRAIL displays also non-apoptotic effects. Mechanisms of such divergence were studied on human endothelial cells and in the chick embryo angiogenesis model. TRAIL promoted both mitogenesis and migration of endothelial cells, by modulation of caspase-8-c-FLIP_L interactions, and, moreover, induced significant angiogenesis in the chick embryo. Proangiogenic effects of TRAIL could thus represent a clou for pharmacological intervention.