Ky-2, a hybrid compound histone deacetylase inhibitor, regulated inflammatory response in LPS-driven human macrophages
Ky-2, a hybrid compound histone deacetylase inhibitor, regulated inflammatory response in LPS-driven human macrophages
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DOI：
10.1002/cbin.11058
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发表时间：
2018-12-01
影响因子：
3.9
通讯作者：
Nishihara, Tatsuji
中科院分区：
文献类型：
--
作者：
Kaneko, Junya;Okinaga, Toshinori;Nishihara, Tatsuji
组蛋白去乙酰化酶作为一种表观遗传因子受到广泛关注，调控组蛋白和转录因子的乙酰化状态对于调控基因表达具有重要意义。此外，组蛋白去乙酰化酶抑制剂参与细胞生长和分化。在本研究中，我们研究了混合化合物HDAC抑制剂Ky-2对体外炎症反应和巨噬细胞极化的影响。人单核细胞样THP-1细胞用佛波醇12-肉豆蔻酸酯13-乙酸酯极化为巨噬细胞样细胞，然后用LPS极化为M1巨噬细胞。Ky-2抑制HDAC 2表达，并增强组蛋白H3的乙酰化。它还下调THP-1细胞中IL-1 β编码基因的表达和LPS诱导的p38丝裂原活化蛋白激酶的磷酸化。此外，Ky-2处理的THP-1细胞中的caspase-1 p20和caspase-3样受体蛋白3的表达下调。与此相反，该试剂上调LPS处理的THP-1细胞中IL-1 ra的表达。这些结果表明，Ky-2处理下调LPS处理的THP-1细胞中炎性细胞因子IL-1 β的表达，表明Ky-2可能通过抑制炎性反应如NLRP 3炎性体活化来调节M1巨噬细胞极化。
Histone deacetylase has attracted much attention as an epigenetic factor, and the modulation of histone and transcription factor acetylation status is important for regulating gene expression. Moreover, histone deacetylase inhibitors are involved in cellular growth and differentiation. In the present study, we examined the effects of Ky-2, a hybrid-compound HDAC inhibitor, on inflammatory reactions and the polarization of macrophages in vitro. Human monocyte-like THP-1 cells were polarized to macrophage-like cells using phorbol 12-myristate 13-acetate, and then polarized to M1 macrophages with LPS. Ky-2 inhibited HDAC2 expression and enhanced the acetylation of histone H3 in THP-1 cells. It also downregulated the expression of the IL-1 beta-encoding gene and the LPS-induced phosphorylation of p38 mitogen-activated protein kinases in THP-1 cells. Moreover, the expression of nod-like receptor protein 3 and cleaved caspase-1 p20 was downregulated in Ky-2-treated THP-1 cells. In contrast, this agent upregulated the expression of IL-1ra in LPS-treated THP-1 cells. These results indicate that Ky-2-treatment downregulates the expression of the inflammatory cytokine, IL-1 beta, in LPS-treated THP-1 cells, suggesting that Ky-2 might regulate M1 macrophage polarization through the suppression of inflammatory responses such as NLRP3 inflammasome activation.