Critical Role of TAK1-Dependent Nuclear Factor-kappa B Signaling in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced Astrocyte Activation and Subsequent Neuronal Death
Critical Role of TAK1-Dependent Nuclear Factor-kappa B Signaling in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced Astrocyte Activation and Subsequent Neuronal Death
复制标题
TAK1 依赖性核因子-κ B 信号传导在 2,3,7,8-四氯二苯并-对-二恶英诱导的星形胶质细胞激活和随后的神经元死亡中的关键作用
DOI：
10.1007/s11064-015-1585-2
复制
发表时间：
2015
影响因子：
4.4
通讯作者：
Wu Qiyun
中科院分区：
文献类型：
--
作者：
Wan Chunhua;Zhang Yang;Jiang Junkang;Jiang Shengyang;Nie Xiaoke;Li Aihong;Guo Aisong;Wu Qiyun
最近发现，2，3，7，8-四氯二苯并对二恶英(TCDD)可在多种细胞中引起炎症反应。然而，TCDD是否能引起星形胶质细胞的炎症反应仍是个未知数。星形胶质细胞是中枢神经系统(CNS)中含量最丰富的胶质细胞。在本研究中，我们发现TCDD暴露可以在体内和体外诱导明显的星形胶质细胞激活。此外，我们还发现，在TCDD诱导的反应性星形胶质细胞的过程中，转化生长因子-β-激活的蛋白1(Tak1)作为一种重要的核因子-κB信号调节因子，被迅速磷酸化。TCDD可导致Tak1和NF-κBp65的快速磷酸化，以及IkBα的降解。此外，用siRNA寡核苷酸或TAK1抑制剂5Z-7-oxozeaenol阻断TAK1可显著抑制TCDD诱导的星形胶质细胞活化和释放肿瘤坏死因子-α。TCDD处理的星形胶质细胞条件培养液可促进PC12神经细胞的凋亡，这种作用可被TAK1抑制剂阻断。综上所述，TCDD可能通过调节Tak1-NF-κB级联反应促进星形胶质细胞的炎症激活，提示反应性星形胶质细胞可能参与了TCDD对中枢神经系统的不良影响。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been recently shown to elicit inflammatory response in a number of cell-types. However, whether TCDD could provoke inflammation in astrocytes, the most abundant glial cells in central nervous system (CNS), remains virtually unknown. In the present study, we showed that TCDD exposure could induce evident astrocyte activation both in vivo and in vitro. Further, we found that TGF-β-activated kinase 1 (TAK1), a critical regulator of NF-κB signaling, was rapidly phosphorylated in the process of TCDD-induced reactive astroglia. Exposure to TCDD led to rapid TAK1 and NF-κB p65 phosphorylation, as well as IKBα degradation. Moreover, blockage of TAK1 using siRNA oligos or TAK1 inhibitor 5Z-7-oxozeaenol significantly attenuated TCDD-induced astrocyte activation as well as the release of TNF-α. Finally, we showed that the conditioned medium of TCDD-treated astrocytes promoted the apoptosis of PC12 neuronal cells, which could be blocked with the pre-treatment of TAK1 inhibitor. Taken together, these findings suggested that TCDD could promote the inflammatory activation of astrocytes through modulating TAK1-NF-κB cascade, implicating that reactive astrocytes might contribute to TCDD-induced adverse effects on CNS system.