Involvement of caspase 8 and c-FLIPL 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-FLIPL ). 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-FLIPL 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.
Department of Clinical and Molecular Biomedicine, University of Catania Medical School, Italy.
Giuseppina
G
Cantarella
Department of Clinical and Molecular Biomedicine, University of Catania Medical School, Italy.
Giulia
G
Di Benedetto
Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Italy.
Domenico
D
Ribatti
Department of Public Health, University of Parma Medical School, Italy.
Gloria
G
Saccani-Jotti
Department of Clinical and Molecular Biomedicine, University of Catania Medical School, Italy.
Renato
R
Bernardini
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505530:CASP8 protein, human; D053181:Caspase 8
cell migration; chorioallantoic membrane; endothelial cells; proliferation; signal transduction