Department of Occupational and Environmental Health, Fujian Medical University, Fuzhou, 350004, China.
J Appl Toxicol. 2011 Oct;31(7):690-7. doi: 10.1002/jat.1654. Epub 2011 Mar 7.
Manganese has been known to induce neurological disorders similar to Parkinson's disease. One of the features of manganese-induced neurotoxicity is oxidative stress. Accumulating data implicate NF-E2-related factor 2 (Nrf2) as a key regulator in the adaptive survival response to oxidative stress. Recent studies suggest that the activation of Nrf2 is induced by manganese in PC12 cells. In the present study, we investigated possible links between reactive oxygen species (ROS), proteasome or mitogen-activated protein kinase (MAPK) signaling and Nrf2/HO-1 activation in manganese-treated PC12 cells. After MnCl(2) treatment, there was an increase in nuclear localization and subsequent binding of Nrf2 to the antioxidant-responsive element (ARE) and upregulation of heme oxygenase-1 (HO-1) protein in PC12 cells. Pretreatment with N-acetyl cysteine, a scavenger of reactive oxygen species, suppressed MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding and subsequent upregulation of HO-1 expression. However, pretreatment with lactacystin, an inhibitor of proteasome activity, enhanced MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding and subsequent upregulation of HO-1 expression. Pretreatment of cells with a pharmacological inhibitor of MAPK (ERK inhibitor PD 98059, P38 inhibitor SB203580 or JNK inhibitor SP600125) did not affect the MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding or subsequent upregulation of HO-1 expression. These results suggest that Nrf2/HO-1 activation by Mn in PC12 cells is associated with ROS and the ubiquitin-proteasome pathway, not MAPK signaling.
锰已被证实会引起类似帕金森病的神经紊乱。其中一个锰诱导神经毒性的特征是氧化应激。越来越多的数据表明，核因子红细胞 2 相关因子 2（Nrf2）是氧化应激适应性存活反应的关键调节因子。最近的研究表明，Nrf2 的激活是由锰在 PC12 细胞中诱导的。在本研究中，我们研究了在锰处理的 PC12 细胞中活性氧（ROS）、蛋白酶体或丝裂原活化蛋白激酶（MAPK）信号与 Nrf2/HO-1 激活之间的可能联系。在 MnCl2 处理后，PC12 细胞中的 Nrf2 核定位增加，随后与抗氧化反应元件（ARE）结合，并上调血红素加氧酶-1（HO-1）蛋白。用 N-乙酰半胱氨酸（ROS 的清除剂）预处理可抑制 MnCl2 诱导的 Nrf2 激活、Nrf2-ARE 结合增加以及随后的 HO-1 表达上调。然而，用蛋白酶体活性抑制剂（乳胞素）预处理增强了 MnCl2 诱导的 Nrf2 激活、Nrf2-ARE 结合增加以及随后的 HO-1 表达上调。用 MAPK（ERK 抑制剂 PD98059、P38 抑制剂 SB203580 或 JNK 抑制剂 SP600125）的药理抑制剂预处理细胞不会影响 MnCl2 诱导的 Nrf2 激活、Nrf2-ARE 结合增加或随后的 HO-1 表达上调。这些结果表明，Mn 在 PC12 细胞中诱导的 Nrf2/HO-1 激活与 ROS 和泛素蛋白酶体途径有关，而与 MAPK 信号无关。
