Correlation between sustained c-Jun N-terminal protein kinase activation and apoptosis induced by tumor necrosis factor-α in rat mesangial cells
Correlation between sustained c-Jun N-terminal protein kinase activation and apoptosis induced by tumor necrosis factor-α in rat mesangial cells
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DOI：
10.1074/jbc.273.7.4027
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发表时间：
1998-02-13
影响因子：
4.8
通讯作者：
Williamson, JR
中科院分区：
文献类型：
--
作者：
Guo, YL;Baysal, K;Williamson, JR
大鼠系膜细胞通常对肿瘤坏死因子 -α（TNF -α）诱导的凋亡具有抗性。在本报告中，我们表明当用放线菌素D、环己酰亚胺或钒酸盐预处理细胞时，它们可变得对TNF -α的凋亡作用敏感。c - Jun N -末端蛋白激酶（JNK）被认为可介导某些刺激引发的凋亡过程，但其在TNF -α诱导的凋亡中的作用一直存在争议。在系膜细胞对TNF -α诱导的凋亡具有抗性或敏感的条件下，对JNK的激活进行了研究。单独的TNF -α刺激产生一个单一的瞬时JNK活性峰。然而，当细胞用放线菌素D或环己酰亚胺预处理时，TNF -α刺激产生第二个持续的JNK活性峰。当细胞用磷酸酶抑制剂钒酸盐预处理时，TNF -α诱导的JNK激活被大大延长。在所有这三种情况下，持续的JNK激活都与凋亡的起始相关。我们的数据表明，这些试剂诱导的JNK的持续激活可能与阻断使JNK失活的磷酸酶的表达有关。进一步的研究表明，丝裂原活化蛋白激酶磷酸酶 - 1（MKP - 1）的表达由TNF -α诱导，这表明在正常条件下，MKP - 1可能通过防止JNK的长时间激活而参与保护细胞免于凋亡。其他研究表明，由TNF -α刺激的细胞外信号调节蛋白激酶激活不太可能导致系膜细胞对TNF -α细胞毒性的抗性。
Rat mesangial cells are normally resistant to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis, In this report we show that the cells can be made susceptible to the apoptotic effect of TNF-alpha when pretreated with actinomycin D, cycloheximide, or vanadate. c-Jun N-terminal protein kinase (JNK) has been thought to mediate apoptotic processes elicited by some stimuli, but its involvement in TNF-alpha-induced apoptosis has been controversial, JNK activation was investigated under conditions where the mesangial cells were either resistant or susceptible to TNF-alpha-induced apoptosis, TNF-alpha alone stimulated a single transient JNK activity peak, However, when the cells were pretreated with actinomycin D or cycloheximide, TNF-alpha stimulated a second sustained JNK activity peak. When the cells were pretreated with the phosphatase inhibitor vanadate, TNF-alpha-induced JNK activation was greatly prolonged, In all three cases, a sustained JNK activation was associated with the initiation of apoptosis. Our data suggest that a sustained activation of JNK induced by these reagents may be associated with blocking the expression of a phosphatase that inactivates JNK, Further studies reveal that the expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) was induced by TNF-alpha, indicating that MKP-1 may be involved in protecting the cells from apoptosis by preventing a prolonged activation of JNK under normal conditions. Additional studies showed that extracellular signal-regulated protein kinase activation stimulated by TNF-alpha was unlikely to contribute to the resistance of mesangial cells to TNF-alpha cytotoxicity.