Tumor necrosis factor-alpha and ceramide induce cell death through different mechanisms in rat mesangial cells.
Tumor necrosis factor-alpha and ceramide induce cell death through different mechanisms in rat mesangial cells.
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肿瘤坏死因子-α 和神经酰胺通过不同机制诱导大鼠系膜细胞死亡。
DOI：
10.1152/ajprenal.1999.276.3.f390
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Williamson,JR
中科院分区：
文献类型：
--
作者：
Guo,YL;Kang,B;Yang,LJ;Williamson,JR
神经酰胺作为细胞信使介导肿瘤坏死因子-α（TNF-α）诱导的细胞凋亡。基于这一假设，推测某些细胞对TNF-α细胞毒性的抗性是由于TNF-α刺激时神经酰胺产生不足所致。本研究的目的是研究正常情况下对TNF-α诱导的细胞凋亡不敏感的系膜细胞是否存在这种情况。我们的研究结果表明，虽然C2神经酰胺对系膜细胞有毒性，但它诱导的细胞死亡在形态学和生物化学上都不同于存在放线菌酮（CHX）的TNF-α诱导的细胞死亡。C2神经酰胺最明显的作用是引起细胞肿胀，然后破坏细胞膜。C2神经酰胺通过坏死引起细胞死亡，而TNF-α在CHX存在下通过凋亡杀死细胞。C2神经酰胺不能模拟TNF-α对c-Jun氨基末端蛋白激酶和核因子-κB转录因子的激活作用。尽管C2神经酰胺和TNF-α均可激活丝裂原活化蛋白激酶[细胞外信号相关激酶（ERK）]，但从ERK激活的动力学来看，这种激活似乎由不同的机制介导。此外，在CHX存在下，C2神经酰胺和TNF-α诱导的细胞死亡过程中，胞浆磷脂酶A2的裂解显示出不同的模式。目前的研究提供的证据表明，细胞凋亡和坏死使用不同的信号机制，导致细胞死亡。
It has been proposed that ceramide acts as a cellular messenger to mediate tumor necrosis factor-α (TNF-α)-induced apoptosis. Based on this hypothesis, it was postulated that resistance of some cells to TNF-α cytotoxicity was due to an insufficient production of ceramide on stimulation by TNF-α. The present study was initiated to investigate whether this was the case in mesangial cells, which normally are insensitive to TNF-α-induced apoptosis. Our results indicate that although C2ceramide was toxic to mesangial cells, the cell death it induced differed both morphologically and biochemically from that induced by TNF-α in the presence of cycloheximide (CHX). The most apparent effect of C2ceramide was to cause cells to swell, followed by disruption of the cell membrane. It is evident that C2ceramide caused cell death by necrosis, whereas TNF-α in the presence of CHX killed the cells by apoptosis. C2ceramide did not mimic the effects of TNF-α on the activation of c-Jun NH2-terminal protein kinase and nuclear factor-κB transcription factor. Although mitogen-activated protein kinase [extracellular signal-related kinase (ERK)] was activated by both C2ceramide and TNF-α, such activation appeared to be mediated by different mechanisms as judged from the kinetics of ERK activation. Furthermore, the cleavage of cytosolic phospholipase A2during cell death induced by C2ceramide and by TNF-α in the presence of CHX showed distinctive patterns. The present study provides evidence that apoptosis and necrosis use distinctive signaling machinery to cause cell death.
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