Increased Nuclear Thioredoxin-1 Potentiates Cadmium-Induced Cytotoxicity
Increased Nuclear Thioredoxin-1 Potentiates Cadmium-Induced Cytotoxicity
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DOI：
10.1093/toxsci/kfs271
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发表时间：
2013-01-01
影响因子：
3.8
通讯作者：
Jones, Dean P.
中科院分区：
文献类型：
--
作者：
Go, Young-Mi;Orr, Michael;Jones, Dean P.
镉（Cd）是一种广泛分布的环境因子，通过对硫氧还蛋白-1（Trx 1）敏感的机制引起氧化毒性。Trx 1是一种细胞质蛋白，在氧化应激过程中易位到细胞核。最近的研究表明，Trx 1与肌动蛋白的相互作用在细胞存活中起着关键作用，并且在细胞和小鼠模型中，核Trx-1的增加增强了促炎信号传导和死亡。这些观察结果表明，低剂量镉引起的氧化毒性可能涉及破坏肌动蛋白-Trx 1相互作用，核Trx 1易位，并增强促炎细胞死亡机制。在这项研究中，我们研究了核定位的Trx 1在镉诱导的炎症和细胞毒性的作用，在体外和体内模型。结果表明，Cd刺激了NF-B的Trx 1和p65的核转位。Trx 1在体外细胞核和转基因小鼠肾脏中的升高增强了Cd刺激的NF-B活化和细胞死亡。Cd刺激的Trx 1核转位和NF-B激活被肌动蛋白聚合抑制剂细胞松弛素D抑制，表明肌动蛋白调节Cd刺激的Trx 1核转位和NF-B激活。核靶向显性负性形式的Trx 1阻断镉刺激的NF-B活化并减少细胞死亡。此外，锌，已知拮抗镉毒性增加金属硫蛋白，镉刺激的核转位的Trx 1和NF-B激活没有影响。两者合计，结果表明，核转位和积累的氧化还原活性Trx 1在细胞核中发挥重要作用，镉诱导的炎症和细胞死亡。
Cadmium (Cd) is a widely dispersed environmental agent that causes oxidative toxicity through mechanisms that are sensitive to thioredoxin-1 (Trx1). Trx1 is a cytoplasmic protein that translocates to nuclei during oxidative stress. Recent research shows that interaction of Trx1 with actin plays a critical role in cell survival and that increased nuclear Trx-1 potentiates proinflammatory signaling and death in cell and mouse models. These observations indicate that oxidative toxicity caused by low-dose Cd could involve disruption of actin-Trx1 interaction, nuclear Trx1 translocation, and potentiation of proinflammatory cell death mechanisms. In this study, we investigated the role of nuclei-localized Trx1 in Cd-induced inflammation and cytotoxicity using in vitro and in vivo models. The results show that Cd stimulated nuclear translocation of Trx1 and p65 of NF-B. Elevation of Trx1 in nuclei in in vitro cells and kidney of transgenic mice potentiated Cd-stimulated NF-B activation and cell death. Cd-stimulated Trx1 nuclear translocation and NF-B activation were inhibited by cytochalasin D, an inhibitor of actin polymerization, suggesting that actin regulates Trx1 nuclear translocation and NF-B activation by Cd. A nuclear-targeted dominant negative form of Trx1 blocked Cd-stimulated NF-B activation and decreased cell death. Addition of zinc, known to antagonize Cd toxicity by increasing metallothionein, had no effect on Cd-stimulated nuclear translocation of Trx1 and NF-B activation. Taken together, the results show that nuclear translocation and accumulation of redox-active Trx1 in nuclei play an important role in Cd-induced inflammation and cell death.