TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation
TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation
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DOI：
10.1038/cdd.2012.90
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发表时间：
2012-12-01
影响因子：
12.4
通讯作者：
Dimanche-Boitrel, M-T
中科院分区：
文献类型：
--
作者：
Jouan-Lanhouet, S.;Arshad, M. I.;Dimanche-Boitrel, M-T
尽管TRAIL（肿瘤坏死因子（TNF）相关的细胞凋亡诱导配体）是一种众所周知的细胞凋亡诱导剂，但我们之前已经证明，在人HT 29结肠和HepG 2中，酸性细胞外pH（pHe）将TRAIL诱导的细胞凋亡转变为调节性坏死（或坏死性凋亡）。肝癌细胞。在这里，我们研究了RIPK 1（受体相互作用蛋白激酶1），RIPK 3和PARP-1（聚（ADP-核糖）聚合酶-1）在TRAIL诱导的坏死性凋亡在体外和刀豆球蛋白A（Con A）诱导的小鼠肝炎的作用。用RIPK 1或PARP-1的药理学抑制剂（分别为Nec-1或PJ-34）预处理HT 29或HepG 2，或用针对RIPK 1或RIPK 3的siRNA瞬时转染，可抑制TRAIL诱导的坏死性凋亡和PARP-1依赖性细胞内ATP耗竭，表明RIPK 1和RIPK 3参与PARP-1激活和ATP耗竭的上游。在Con A诱导的肝炎小鼠模型中，小鼠肝细胞的死亡依赖于TRAIL和NKT（自然杀伤T）细胞，PARP-1活性与肝损伤呈正相关，Nec-1或PJ-34均可预防肝炎。这些数据为TRAIL诱导的坏死性凋亡提供了新的见解，其中PARP-1是RIPK 1/RIPK 3引发剂下游的活性效应子，并表明RIPKs和PARP-1的药理学抑制剂可能是免疫介导的肝炎的新治疗选择。Cell Death and Differentiation（2012）19，2003-2014; doi：10.1038/cdd.2012.90; 2012年7月20日在线发表
Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAIL-induced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis. Cell Death and Differentiation (2012) 19, 2003-2014; doi:10.1038/cdd.2012.90; published online 20 July 2012