Proteomic Analysis of HDAC3 Selective Inhibitor in the Regulation of Inflammatory Response of Primary Microglia.
Proteomic Analysis of HDAC3 Selective Inhibitor in the Regulation of Inflammatory Response of Primary Microglia.
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HDAC3 选择性抑制剂调节原代小胶质细胞炎症反应的蛋白质组学分析
DOI：
10.1155/2017/6237351
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发表时间：
2017
影响因子：
3.1
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Xia M;Zhao Q;Zhang H;Chen Y;Yuan Z;Xu Y;Zhang M
HDAC 3已被证明可以调节炎症。然而，HDAC 3在原发性小胶质细胞中的作用在很大程度上是未知的。RGFP 966是一种新发现的选择性HDAC 3抑制剂。在这项研究中，我们使用蛋白质质谱分析蛋白质的变化，在LPS处理的原代小胶质细胞与应用RGFP 966。研究了大约2000种蛋白质。444个LPS诱导蛋白中有168个（37.8%）在RGFP 966处理后显著降低，主要集中在Toll样受体信号通路上。在这方面，我们选择了Toll样受体2（TLR 2）、TLR 3、TLR 6、MAPK p38、CD 36和脾酪氨酸激酶（SYK）进行进一步验证，发现它们在LPS刺激后均显著上调，在RGFP 966存在下下调。此外，RGFP 966抑制上清液肿瘤坏死因子（TNF）-α和白细胞介素6（IL-6）浓度。在LPS刺激后2 h，STAT 3和STAT 5的激活被RGFP 966部分阻断。在LPS + RGFP 966处理组中，CD 16/32的荧光强度显著降低。总之，我们的数据提示RGFP 966可能是一种潜在的治疗药物，可对抗中枢神经系统小胶质细胞活化和炎症反应，这可能与其对TLR信号通路和STAT 3/STAT 5通路的抑制作用有关。
HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway. In this regard, we selected Toll-like receptor 2 (TLR2), TLR3, TLR6, MAPK p38, CD36, and spleen tyrosine kinase (SYK) for further validation and found that they were all significantly upregulated after LPS stimulation and downregulated in the presence of RGFP966. Additionally, RGFP966 inhibited supernatant tumor necrosis factor (TNF)-α and Interleukin 6 (IL-6) concentrations. Activation of STAT3 and STAT5 was partially blocked by RGFP966 at 2 h after LPS-stimulation. The fluorescence intensity of CD16/32 was significantly decreased in LPS + RGFP966-treated group. In conclusion, our data provided a hint that RGFP966 may be a potential therapeutic medication combating microglia activation and inflammatory response in central nervous system, which was probably related to its repressive impacts on TLR signaling pathways and STAT3/STAT5 pathways.