Liu Xiaoling, Yao Chunyan, Tang Yan, Liu Xiaoyan, Duan Chenggang, Wang Chunmei, Han Fei, Xiang Ying, Wu Long, Li Yafei, Ji Ailing, Cai Tongjian
Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China.
Experimental Teaching Center, School of Public Health, Southwest Medical University, Luzhou, China.
Ecotoxicol Environ Saf. 2022 Aug;241:113824. doi: 10.1016/j.ecoenv.2022.113824. Epub 2022 Jul 4.
Manganese (Mn) is an essential cofactor for many enzymes and plays an important role in normal growth and development. However, excess exposure to manganese (Mn) may be an important environmental factor leading to neurodegeneration. The overexpression of microglial cyclooxygenase-2 (COX-2) plays a key role in neuroinflammation in neurodegenerative diseases. The existing data suggest that Mn can induce neuroinflammation by up-regulating COX-2 expression. However, the mechanisms involved in Mn-induced microglial COX-2 up-regulation remain to be determined. The aim of this study was to investigate the role of p53 in Mn-induced COX-2 expression in microglial cells. The results showed that Mn exposure induced the up-regulation of COX-2 and inhibited the expression of p53 in BV2 microglial cells. The addition of p53 activator and the over-expression of p53 blocked the expression of COX-2 and prostaglandin E2 (PGE2), a COX-2 downstream effector, induced by Mn. Further, Mn increased the methylation of p53 DNA in microglia, while the addition of demethylation reagent 5-Aza-dC enhanced the expression of p53 but decreased the expression of COX-2. These results suggested that Mn may inhibit p53 expression through induction of DNA methylation, which can further induce the expression of COX-2 in microglial cells.
锰（Mn）是许多酶的必需辅助因子，在正常生长发育中起重要作用。然而，过量接触锰可能是导致神经退行性变的一个重要环境因素。小胶质细胞环氧化酶-2（COX-2）的过度表达在神经退行性疾病的神经炎症中起关键作用。现有数据表明，锰可通过上调COX-2表达诱导神经炎症。然而，锰诱导小胶质细胞COX-2上调的机制仍有待确定。本研究的目的是探讨p53在锰诱导小胶质细胞COX-2表达中的作用。结果表明，锰暴露诱导BV2小胶质细胞中COX-2上调并抑制p53表达。添加p53激活剂和p53过表达可阻断锰诱导的COX-2及COX-2下游效应分子前列腺素E2（PGE2）的表达。此外，锰增加了小胶质细胞中p53 DNA的甲基化，而添加去甲基化试剂5-氮杂-2'-脱氧胞苷可增强p53表达但降低COX-2表达。这些结果表明，锰可能通过诱导DNA甲基化抑制p53表达，进而诱导小胶质细胞中COX-2的表达。
