2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces microglial nitric oxide production and subsequent rat primary cortical neuron apoptosis through p38/JNK MAPK pathway
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces microglial nitric oxide production and subsequent rat primary cortical neuron apoptosis through p38/JNK MAPK pathway
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2,3,7,8-四氯二苯并-对二恶英 (TCDD) 通过 p38/JNK MAPK 途径诱导小胶质细胞一氧化氮的产生以及随后的大鼠原代皮质神经元凋亡
DOI：
10.1016/j.tox.2013.08.008
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发表时间：
2013-10-04
期刊：
影响因子：
4.5
通讯作者：
Xu, Guangfei
中科院分区：
文献类型：
--
作者：
Li, Yuanye;Chen, Gang;Xu, Guangfei
人们普遍认为，小胶质细胞是大脑中的先天免疫细胞，激活后会导致神经元损伤。在本研究中，我们研究了 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 在调节小胶质细胞一氧化氮产生中的作用及其在引起神经元损伤中的作用。研究表明，TCDD 以剂量和时间依赖性方式刺激诱导型一氧化氮合酶 (iNOS) 的表达以及一氧化氮 (NO) 的产生。此外，在 TCDD 治疗后，HAPI 小胶质细胞中发现 p38 和 JNK MAPK 快速激活。用特定抑制剂 SB202190 和 SP600125 阻断 p38 和 JNK 激酶，可显着降低 TCDD 诱导的 iNOS 表达和 NO 产生。此外，通过用经 TCDD 处理的小胶质细胞调节的培养基处理大鼠原代皮层神经元，证明小胶质细胞 iNOS 激活介导神经元凋亡。最后，还发现 p38 和 JNK MAPK 抑制剂在暴露于经 TCDD 处理的 HAPI 小胶质细胞条件培养基后可以减弱大鼠皮质神经元的凋亡。基于这些观察，我们强调 p38/JNK MAPK 通路在 TCDD 诱导的大鼠 HAPI 小胶质细胞 iNOS 激活以及随后诱导原代皮质神经元凋亡中发挥重要作用。 (C) 2013 Elsevier Ireland Ltd. 保留所有权利。
It has been widely accepted that microglia, which are the innate immune cells in the brain, upon activation can cause neuronal damage. In the present study, we investigated the role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in regulating microglial nitric oxide production and its role in causing neuronal damage. The study revealed that TCDD stimulates the expression of inducible nitric oxide synthase (iNOS) as well as the production of nitric oxide (NO) in a dose- and time-dependent manner. Further, a rapid activation of p38 and JNK MAPKs was found in HAPI microglia following TCDD treatment. Blockage of p38 and JNK kinases with their specific inhibitors, SB202190 and SP600125, significantly reduced TCDD-induced iNOS expression and NO production. In addition, it was demonstrated through treating rat primary cortical neurons with media conditioned with TCDD treated microglia that microglial iNOS activation mediates neuronal apoptosis. Lastly, it was also found that p38 and JNK MAPK inhibitors could attenuate the apoptosis of rat cortical neurons upon exposure to medium conditioned by TCDD-treated HAPI microglial cells. Based on these observations, we highlight that the p38/JNK MAPK pathways play an important role in TCDD-induced iNOS activation in rat HAPI microglia and in the subsequent induction of apoptosis in primary cortical neurons. (C) 2013 Elsevier Ireland Ltd. All rights reserved.