Methylmercury induces the expression of chemokine CCL4 via SRF activation in C17.2 mouse neural stem cells
Methylmercury induces the expression of chemokine CCL4 via SRF activation in C17.2 mouse neural stem cells
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甲基汞通过 SRF 激活 C17.2 小鼠神经干细胞诱导趋化因子 CCL4 的表达
DOI：
10.1038/s41598-019-41127-y
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发表时间：
2019
影响因子：
4.6
通讯作者：
Gi-Wook Hwang
中科院分区：
文献类型：
--
作者：
Min-Seok Kim;Tsutomu Takahashi;Jin-Yong Lee;Takashi Toyama;Takayuki Hoshi;Shusuke Kuge;Yasuyuki Fujiwara;Akira Naganuma;Gi-Wook Hwang
甲基汞是一种环境污染物，对中枢神经系统造成特定和严重的损害。我们以前已经表明，C-C基序趋化因子配体4（CCL 4）保护培养的神经细胞免受甲基汞毒性和CCL 4的表达是特异性诱导小鼠脑甲基汞。在这项研究中，我们研究了转录调控机制，诱导CCL 4表达甲基汞使用C17.2小鼠神经干细胞。报告基因分析表明，甲基汞诱导CCL 4基因表达需要转录起始位点上游50 bp的区域。选择了九种可能与该上游区域结合并参与甲基汞诱导CCL 4表达的转录因子，并通过敲低血清反应因子（SRF）来抑制甲基汞对CCL 4表达的诱导。此外，甲基汞还能提高SRF在细胞核中的表达水平，并使与CCL 4基因启动子结合的量增加。此外，我们研究了参与SRF诱导CCL 4表达的上游信号通路，并证实参与MAPK通路的一部分p38和ERK的激活。这些结果表明，甲基汞通过激活SRF通过p38和ERK信号通路诱导CCL 4的表达。我们的研究结果是重要的阐明机制参与脑特异性诱导CCL 4的表达甲基汞。
Methylmercury is an environmental pollutant that causes specific and serious damage to the central nervous system. We have previously shown that C-C motif chemokine ligand 4 (CCL4) protects cultured neural cells from methylmercury toxicity and expression of CCL4 is specifically induced in mouse brain by methylmercury. In this study, we examined the transcriptional regulatory mechanism that induces CCL4 expression by methylmercury using C17.2 mouse neural stem cells. The promoter region of theCCL4gene was analyzed by a reporter assay, revealing that the region up to 50 bp upstream from the transcription start site was necessary for inducing expression of CCL4 by methylmercury. Nine transcription factors that might bind to this upstream region and be involved in the induction of CCL4 expression by methylmercury were selected, and the induction of CCL4 expression by methylmercury was suppressed by the knockdown of serum response factor (SRF). In addition, the nuclear level of SRF was elevated by methylmercury, and an increase in the amount bound to theCCL4gene promoter was also observed. Furthermore, we examined the upstream signaling pathway involved in the induction of CCL4 expression by SRF, and confirmed that activation of p38 and ERK, which are part of the MAPK pathway, are involved. These results suggest that methylmercury induces the expression of CCL4 by activating SRF via the p38 and ERK signaling pathway. Our findings are important for elucidating the mechanism involved in the brain-specific induction of CCL4 expression by methylmercury.