Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, 803-8580, Japan.
School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Fukuoka, 803-8580, Japan.
Cell Biol Int. 2018 Dec;42(12):1622-1631. doi: 10.1002/cbin.11058. Epub 2018 Oct 5.
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-1β-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-1β, 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.
组蛋白去乙酰化酶作为一种表观遗传因子备受关注，组蛋白和转录因子乙酰化状态的调节对于基因表达的调控非常重要。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 Ky-2（一种混合化合物 HDAC 抑制剂）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 13-乙酸盐（PMA）极化成为巨噬细胞样细胞，然后用 LPS 极化成为 M1 巨噬细胞。Ky-2 抑制 HDAC2 的表达并增强 THP-1 细胞中组蛋白 H3 的乙酰化。它还下调了 THP-1 细胞中 IL-1β 编码基因的表达和 LPS 诱导的 p38 丝裂原活化蛋白激酶磷酸化。此外，Ky-2 处理的 THP-1 细胞中 nod-like 受体蛋白 3 和切割的半胱天冬酶-1 p20 的表达下调。相反，该药物上调了 LPS 处理的 THP-1 细胞中 IL-1ra 的表达。这些结果表明，Ky-2 处理下调了 LPS 处理的 THP-1 细胞中炎症细胞因子 IL-1β 的表达，表明 Ky-2 可能通过抑制 NLRP3 炎性体激活等炎症反应来调节 M1 巨噬细胞极化。
