Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes
Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes
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DOI：
10.1189/jlb.6ab0914-416r
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发表时间：
2015-07-01
影响因子：
5.5
通讯作者：
Netea, Mihai G.
中科院分区：
文献类型：
--
作者：
Arts, Rob J. W.;Blok, Bastiaan A.;Netea, Mihai G.
流行病学研究表明，VAS具有持久的免疫调节作用。我们假设ATRA通过组蛋白修饰诱导表观遗传重编程，抑制单核细胞免疫训练模型中的炎性细胞因子。我们使用了先前描述的训练免疫的体外模型，其中健康志愿者的粘附单核细胞与BCG在ATRA的存在或不存在下孵育24小时。清洗细胞后，将它们在培养基中再孵育6天，并用微生物配体重新刺激，并评估细胞因子的产生。ATRA抑制单核细胞再刺激后的细胞因子反应，这种作用是通过增加SUV39H2的表达来实现的，SUV39H2是一种诱导抑制性标记H3K9me3的组蛋白甲基转移酶。ATRA上调了几种细胞因子启动子位点的H3K9me3，抑制SUV 39 H2恢复了细胞因子的产生。除H3K9me3外，刺激性组蛋白标记H3K4me3在细胞因子基因的几个启动子位置被ATRA下调。因此，我们可以得出结论，全反式维甲酸抑制细胞因子的生产模型中的直接刺激或卡介苗诱导的训练免疫，这些影响是由组蛋白修饰介导的。
Epidemiologic studies suggest that VAS has long-lasting immunomodulatory effects. We hypothesized that ATRA inhibits inflammatory cytokines in a model of trained immunity in monocytes by inducing epigenetic reprogramming through histone modifications. We used an previously described in vitro model of trained immunity, in which adherent monocytes of healthy volunteers were incubated for 24 h with BCG in the presence or absence of ATRA. After washing the cells, they were incubated for an additional 6 d in culture medium and restimulated with microbial ligands, and cytokine production was assessed. ATRA inhibited cytokine responses upon restimulation of monocytes, and this effect was exerted through increased expression of SUV39H2, a histone methyltransferase that induces the inhibitory mark H3K9me3. H3K9me3 at promoter sites of several cytokines was up-regulated by ATRA, and inhibition of SUV39H2 restored cytokine production. In addition to H3K9me3, the stimulatory histone mark H3K4me3 was down-regulated by ATRA at several promoter locations of cytokine genes. Therefore, we can conclude that ATRA inhibits cytokine production in models of direct stimulation or BCG-induced trained immunity and that these effects are mediated by histone modifications.