Involvement of caspase 8 and c-FLIPL in the proangiogenic effects of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)
Involvement of caspase 8 and c-FLIPL in the proangiogenic effects of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)
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DOI：
10.1111/febs.12720
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发表时间：
2014-03-01
期刊：
影响因子：
5.4
通讯作者：
Bernardini, Renato
中科院分区：
文献类型：
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作者：
Cantarella, Giuseppina;Di Benedetto, Giulia;Bernardini, Renato
肿瘤坏死因子相关凋亡诱导配体（TRAIL），肿瘤坏死因子超家族的细胞因子，是一种有效的细胞凋亡诱导剂，尽管其作用随浓度而变化。事实上，低浓度的TRAIL与非凋亡效应相关，例如细胞增殖。在这里，不同浓度的TRAIL对体外人脐静脉内皮细胞（HUVEC）的有丝分裂和迁移的影响进行了评估，以及在鸡胚绒毛尿囊膜（CAM）血管生成模型体内。在低浓度下，TRAIL促进HUVEC的有丝分裂或迁移，使用伤口愈合方法进行评估。沿着caspase 8样分子、细胞FLICE抑制蛋白（长型）（c-FLIPL）的表达，评估了caspase 8的切割。低浓度的TRAIL不能诱导caspase 8的加工，而高浓度的TRAIL诱导HUVEC凋亡和caspase 8的激活。此外，TRAIL诱导一个显着的血管生成反应，在CAM测定体内，与血管内皮生长因子。这些数据表明，TRAIL的非凋亡作用包括有丝分裂和增加内皮细胞的流动性，并最终血管生成。此外，结果表明c-FLIPL水平也受到TRAIL浓度差异的调节，表明其参与了TRAIL的发散效应。总之，这项研究设想了促血管生成的作用，TRAIL，这表明TRAIL可能代表一个目标的药理学操作。
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) invitro, as well as in the chick embryo chorioallantoic membrane (CAM) angiogenesis model invivo. At low concentrations, TRAIL promoted either mitogenesis or migration of HUVEC, evaluated using the wound healing method. Cleavage of caspase8 was evaluated along with expression of the caspase8-like molecule, cellular FLICE-inhibitory protein (long form) (c-FLIPL). Low concentrations of TRAIL failed to induce caspase8 processing, whereas high concentrations induced apoptosis of HUVEC and activation of caspase8. Moreover, TRAIL induced a significant angiogenic response in the CAM assay invivo, 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.