Induction of Adaptive Response and Enhancement of PC12 Cell Tolerance by 7-Hydroxycholesterol and 15-Deoxy-Δ12,14-Prostaglandin J2 through Up-regulation of Cellular Glutathione via Different Mechanisms
Induction of Adaptive Response and Enhancement of PC12 Cell Tolerance by 7-Hydroxycholesterol and 15-Deoxy-Δ12,14-Prostaglandin J2 through Up-regulation of Cellular Glutathione via Different Mechanisms
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DOI：
10.1074/jbc.m600260200
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发表时间：
2006-05-19
影响因子：
4.8
通讯作者：
Niki, Etsuo
中科院分区：
文献类型：
--
作者：
Chen, Zhi-Hua;Yoshida, Yasukazu;Niki, Etsuo
越来越多的证据表明，活性氧和其他生理上存在的氧化刺激诱导的适应性反应。我们最近报道了多种脂质过氧化产物在亚致死浓度下可以诱导适应性反应并增强PC 12细胞的耐受性，尽管详细的潜在分子机制尚未明确阐明。在本研究中，我们发现7-羟基胆固醇（7-OHCh）和15-脱氧-δ（12，14）-前列腺素J（2）（15 d-PGJ（2））在亚致死浓度下均显著增加细胞GSH以及GSH合成的限速酶谷氨酸-半胱氨酸连接酶（GCL）的酶活性。细胞GSH的丁噻呋砜亚胺耗尽完全取消了适应性反应。有趣的是，15 d-PGJ（2）处理以NF-E2相关因子2（Nrf 2）依赖的方式显著增加GCL两个亚基的基因表达，而7-OHCh既没有诱导GCL基因表达的任何显著变化，也没有Nrf 2-小干扰RNA处理对7-OHCh诱导的GSH升高和随后的适应性反应产生任何明显影响。这些结果表明，7-OHCh和15 d-PGJ（2）诱导的适应性反应类似地通过GSH的上调介导，但通过不同的机制。
Increasing evidence suggests an adaptive response induced by reactive oxygen species and other physiologically existing oxidative stimuli. We have recently reported that a variety of lipid peroxidation products at sublethal concentrations could induce adaptive response and enhance PC12 cell tolerance, although the detailed underlying molecular mechanisms have not been clearly clarified. In the present study, we found that both 7-hydroxycholesterol (7-OHCh) and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) at sublethal concentrations significantly increased the cellular GSH as well as the enzyme activity of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of GSH synthesis. Depletion of cellular GSH by buthionine sulfoximine completely abolished the adaptive response. Interestingly, treatment with 15d-PGJ(2) significantly increased the gene expression of both subunits of GCL in an NF-E2-related factor 2 (Nrf2)-dependent manner, whereas neither 7-OHCh induced any considerable changes on the GCL gene expression nor did the Nrf2-small interfering RNA treatment exert any appreciable effects on the GSH elevation and subsequent adaptive response induced by 7-OHCh. These results demonstrate that the adaptive response induced by both 7-OHCh and 15d-PGJ(2) is mediated similarly through the up-regulation of GSH but via different mechanisms.