Inhibition of KDM4A activity as a strategy to suppress interleukin-6 production and attenuate colitis induction
Inhibition of KDM4A activity as a strategy to suppress interleukin-6 production and attenuate colitis induction
复制标题
DOI：
10.1016/j.clim.2017.05.014
复制
发表时间：
2017-07-01
影响因子：
8.6
通讯作者：
Hirooka, Yoshiki
中科院分区：
文献类型：
--
作者：
Ishiguro, Kazuhiro;Watanabe, Osamu;Hirooka, Yoshiki
4-氯-7-硝基-2,1,3-苯并恶二唑（NBD-CI）作为半抗原与蛋白质结合后发出荧光。因此，半抗原蛋白的荧光可视化是NBD-Cl诱导结肠炎的一个特征。利用该结肠炎模型，我们将结肠炎诱导时激活的成纤维细胞定位在半抗原蛋白附近，并观察到激活的成纤维细胞中产生白细胞介素(IL)-6。我们用肿瘤坏死因子α (tnf - α)刺激原代成纤维细胞筛选草药成分，发现苍术素对IL-6的产生有抑制作用。在tnf - α刺激下，白术素诱导组蛋白H3在赖氨酸残基9处三甲基化，从而破坏NF-kappa B与基因组DNA上IL-6启动子的结合。苍术素抑制KDM4A活性，但不抑制KDM6A活性。白术素减轻结肠炎诱导。KDM4A抑制剂ML324对IL-6的产生和结肠炎的诱导具有相似的作用。我们提出抑制KDM4A活性作为抑制IL-6产生和减轻结肠炎诱导的策略。(C) 2017爱思唯尔公司版权所有。
4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-CI) functions as a hapten and fluoresces upon binding to proteins. Therefore, fluorescence visualization of hapten-proteins is a feature of the colitis induced by NBD-Cl. Using this colitis model, we located activated fibroblasts in the vicinity of hapten-proteins upon colitis induction and observed interleukin (IL)-6 production in the activated fibroblasts. We screened herbal ingredients using primary fibroblasts stimulated with tumor necrosis factor alpha (TNF-alpha) and found the suppressive action of Atractylodin on IL-6 production. Under TNF-alpha stimulation, Atractylodin induced the tri-methylation of histone H3 at lysine residue 9, which impaired the binding between NF-kappa B and the IL-6 promoter on the genomic DNA. Atractylodin inhibited KDM4A but not KDM6A activity. Atractylodin administration attenuated colitis induction. The KDM4A inhibitor ML324 showed similar actions on IL-6 production and colitis induction. We propose the inhibition of KDM4A activity as a strategy to suppress IL-6 production and attenuate colitis induction. (C) 2017 Elsevier Inc. All rights reserved.