Department of Respiratory Medicine, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Int J Immunopathol Pharmacol. 2013 Apr-Jun;26(2):371-81. doi: 10.1177/039463201302600210.
Asthma is an inflammatory disease of the airways, and the current treatment in managing asthma is the control of inflammation. Notch signaling pathway has been linked to T-cell imbalance. The present study aimed to explore the histone modifications of Notch1 promoter in normal and asthmatic lung CD4+ T cells. Chromatin immunoprecipitation analysis showed that the acetylation levels of total H3, H4, site-specific H3K9, H3K14, H3K27, H3K18, H4K16, and the trimethylation levels of H3K4, H3K79 of Notch1 gene promoter were increased significantly in asthmatic lung CD4+ T cells compared to the control group, which correlated with increased P300, PCAF activity and decreased HDAC1, HDAC2 activity. After intervention of garcinol, a potent inhibitor of histone acetyltransferases, in asthmatic lung CD4+ T cells, HAT activity decreased significantly and the increased Notch1 and hes-1 expression was reversed. The total H3ac, H4ac, site-specific H3K9ac, H3K14ac, H3K27ac, H3K18ac, H4K16ac and H3K79me3 levels of Notch1 gene promoter decreased significantly, and the H3K4me3, H3K9me3, H4K20me3 levels had no significant difference. We further investigated the suppressive effects of GAR on asthmatic parameters. Results showed that the levels of IL-4, IL-5 and IL-13 were significantly reduced and a small reverse trend was found in the level of IFN-g after GAR treatment. Furthermore, the expression of NF-κB and AP-1 reduced significantly. These results suggest that asthma is associated with changes in the epigenetic status of Notch1 promoter, including abnormal histone acetylation and methylation, and GAR may have applications in the treatment of asthma.
哮喘是一种气道炎症性疾病，目前哮喘的治疗主要是控制炎症。Notch 信号通路与 T 细胞失衡有关。本研究旨在探讨 Notch1 启动子在正常和哮喘肺 CD4+T 细胞中的组蛋白修饰。染色质免疫沉淀分析显示，哮喘肺 CD4+T 细胞中 Notch1 基因启动子的总 H3、H4、特异性 H3K9、H3K14、H3K27、H3K18、H4K16 的乙酰化水平和 H3K4、H3K79 的三甲基化水平显著升高，与 P300、PCAF 活性增加和 HDAC1、HDAC2 活性降低有关。在哮喘肺 CD4+T 细胞中加入 Garcinol 后，一种有效的组蛋白乙酰转移酶抑制剂，HAT 活性显著降低，Notch1 和 hes-1 的表达增加得到逆转。Notch1 基因启动子的总 H3ac、H4ac、特异性 H3K9ac、H3K14ac、H3K27ac、H3K18ac、H4K16ac 和 H3K79me3 水平显著降低，H3K4me3、H3K9me3、H4K20me3 水平无显著差异。我们进一步研究了 GAR 对哮喘参数的抑制作用。结果表明，IL-4、IL-5 和 IL-13 的水平显著降低，GAR 治疗后 IFN-g 的水平出现微小的逆转趋势。此外，NF-κB 和 AP-1 的表达显著降低。这些结果表明，哮喘与 Notch1 启动子表观遗传状态的改变有关，包括异常的组蛋白乙酰化和甲基化，GAR 可能在哮喘治疗中有应用价值。
