Protective effect of NSA on intestinal epithelial cells in a necroptosis model.
Protective effect of NSA on intestinal epithelial cells in a necroptosis model.
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NSA对坏死性凋亡模型肠上皮细胞的保护作用
DOI：
10.18632/oncotarget.21418
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发表时间：
2017-10-17
期刊：
影响因子：
--
通讯作者：
Liang X
中科院分区：
文献类型：
--
作者：
Dong W;Zhang M;Zhu Y;Chen Y;Zhao X;Li R;Zhang L;Ye Z;Liang X
目的采用模拟炎症性肠病（IBD）的坏死性凋亡模型，探讨坏死性凋亡抑制剂坏死磺胺（NSA）对肠上皮细胞的保护作用。方法采用2，4，6-三硝基苯磺酸（TNBS）经直肠灌胃建立BALB/c小鼠结肠炎模型。评估病理损伤和细胞死亡。应用TNF-α和Z-VAD-fetamine建立了一种新的Caco-2细胞坏死性凋亡体外模型，并分别用NSA和非NSA处理。检测细胞形态学变化、细胞死亡方式以及受体相互作用蛋白激酶3（p-RIPK 3）和混合谱系激酶结构域样（p-MLKL）磷酸化水平。结果在TNBS诱导的小鼠结肠炎模型中，肠黏膜中TUNEL阳性细胞和caspase-3阴性细胞，p-RIPK 3表达升高。在TNF-α和Z-VAD-factors刺激下，Caco-2细胞形态学损伤加重，坏死比例增加，p-RIPK 3和p-MLKL水平升高，证实细胞的调节性死亡为坏死性凋亡。NSA可逆转TNF-α和Z-VAD-factorin诱导的细胞形态学异常并减少坏死性细胞死亡。结论NSA可抑制肠上皮细胞坏死性凋亡，对IBD有潜在的保护作用。
Objective This study aimed to investigate the protective effect of the necroptosis inhibitor necrosulfonamide (NSA) on intestinal epithelial cells using a novel in vitro necroptosis model that mimics inflammatory bowel disease (IBD). Methods 2,4,6-trinitrobenzenesulfonic acid (TNBS) was perfused into the rectum of BALB/c mice to established a colitis model. Pathologic injury and cell death were evaluated. A novel in vitro model of necroptosis was established in Caco-2 cells using TNF-α and Z-VAD-fmk, and the cells were treated with or without NSA. Morphologic changes, manner of cell death and the levels of phosphorylation of receptor-interacting protein kinase 3 (p-RIPK3) and mixed-lineage kinase domain-like (p-MLKL) were detected. Results In the TNBS-induced colitis in mice, TUNEL-positive and caspase-3-negative cells were observed in the intestinal mucosa, and p-RIPK3 was found to be elevated. Under the stimulation of TNF-α and Z-VAD-fmk, the morphologic damage in the Caco-2 cells was aggravated, the proportion of necrosis was increased, and the level of p-RIPK3 and p-MLKL were increased, confirming that the regulated cell death was necroptosis. NSA reversed the morphological abnormalities and reduced necrotic cell death induced by TNF-α and Z-VAD-fmk. Conclusion NSA can inhibit necroptosis in intestinal epithelial cells in vitro and might confer a potential protective effect against IBD.
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