2,3,7,8-Tetrachlorodibenzo-p-dioxin stimulates proliferation of HAPI microglia by affecting the Akt/GSK-3尾/cyclin D1 signaling pathway

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• 作者：Guangfei Xu ; Yuanye Li ; Katsuhiko Yoshimoto ; Qiyun Wu ; Gang Chen ; Takeo Iwata ; Noriko Mizusawa ; Chunhua Wan ; Xiaoke Nie
• 关键词：AhR ; aryl hydrocarbon receptor ; CNS ; central nervous system ; EdU ; 5-ethynyl-2&prime ; -deoxyuridine ; ELISA ; enzyme-linked immunosorbent assay ; ERK ; extracellular signal-regulated kinase ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; GSK-3尾 ; glycogen synthase kinase-3尾 ; IL-1尾 ; interleukin-1 beta ; PBS ; phosphate-buffered saline ; PI ; propidium iodide ; PI3K ; phosphoinositide 3-kinase ; RNS ; reactive nitrogen species ; ROS ; reactive oxide species ; RT-PCR ; reverse transcription-polymerase chain reac
• 刊名：Toxicology Letters
• 出版年：30 January, 2014
• 年：2014
• 卷：224
• 期：3
• 页码：362-370
• 全文大小：2252 K

文摘

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxin that induces apoptosis of neurons and a pro-inflammatory response in microglial cells. First, we found that TCDD induced proliferation of HAPI microglial cells in a dose- and time-dependent manner. Flow cytometry analysis showed that this proliferation by TCDD was due to mainly enhancing the G1 to S phase transition. Next, it was found that TCDD treatment led to up-regulation of cyclin D1, which induces cell cycle progression from G1 to S phase, in a time-dependent manner. As for molecular mechanism, we revealed that TCDD was capable of inducing Akt phosphorylation and activation, resulting in phosphorylation and inactivation of glycogen synthase kinase-3尾 (GSK-3尾). Inactivated GSK-3尾 attenuated proteasomal degradation of cyclin D1 by reducing Thr²⁸⁶-phosphorylated cyclin D1 levels. Moreover, inactivated GSK-3尾 increased cyclin D1 gene transcription by increasing its transcription factor 尾-catenin in the nucleus. Further, blockage of phosphoinositide 3-kinase/Akt kinase with their specific inhibitors, LY294002 and Akt 1/2 kinase inhibitor, significantly reduced TCDD-enhanced proliferation of HAPI microglial cells. In conclusion, TCDD stimulates proliferation of HAPI microglial cells by affecting the Akt/GSK-3尾/cyclin D1 signaling pathway.