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慢性酒精暴露后人单核细胞来源树突状细胞中翻译后修饰的新发现：炎症调节因子 H4K12ac 的作用。

Novel detection of post-translational modifications in human monocyte-derived dendritic cells after chronic alcohol exposure: Role of inflammation regulator H4K12ac.

机构信息

Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, United States.

Advanced Mass Spectrometry Facility, Department of Chemistry and Biochemistry, Florida International University, Miami, FL, 33199, United States.

出版信息

Sci Rep. 2017 Sep 11;7(1):11236. doi: 10.1038/s41598-017-11172-6.

DOI:10.1038/s41598-017-11172-6
PMID:28894190
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5593989/
Abstract

Previous reports on epigenetic mechanisms involved in alcohol abuse have focus on hepatic and neuronal regions, leaving the immune system and specifically monocyte-derived dendritic cells (MDDCs) understudied. Our lab has previously shown histone deacetylases are modulated in cells derived from alcohol users and after in vitro acute alcohol treatment of human MDDCs. In the current study, we developed a novel screening tool using matrix assisted laser desorption ionization-fourier transform-ion cyclotron resonance mass spectrometry (MALDI-FT-ICR MS) and single cell imaging flow cytometry to detect post-translational modifications (PTMs) in human MDDCs due to chronic alcohol exposure. Our results demonstrate, for the first time, in vitro chronic alcohol exposure of MDDCs modulates H3 and H4 and induces a significant increase in acetylation at H4K12 (H4K12ac). Moreover, the Tip60/HAT inhibitor, NU9056, was able to block EtOH-induced H4K12ac, enhancing the effect of EtOH on IL-15, RANTES, TGF-β1, and TNF-α cytokines while restoring MCP-2 levels, suggesting that H4K12ac may be playing a major role during inflammation and may serve as an inflammation regulator or a cellular stress response mechanism under chronic alcohol conditions.

摘要

先前关于涉及酒精滥用的表观遗传机制的报告主要集中在肝脏和神经元区域，而免疫系统，特别是单核细胞衍生的树突状细胞（MDDC）研究较少。我们的实验室之前已经表明，在来自酒精使用者的细胞中和体外急性酒精处理人类 MDDC 后，组蛋白去乙酰化酶被调节。在当前的研究中，我们使用基质辅助激光解吸电离-傅里叶变换离子回旋共振质谱（MALDI-FT-ICR MS）和单细胞成像流式细胞术开发了一种新的筛选工具，以检测由于慢性酒精暴露而导致的人 MDDC 中的翻译后修饰（PTM）。我们的结果首次证明，MDDC 的体外慢性酒精暴露调节 H3 和 H4，并诱导 H4K12（H4K12ac）的乙酰化显著增加。此外，Tip60/HAT 抑制剂 NU9056 能够阻断 EtOH 诱导的 H4K12ac，增强 EtOH 对 IL-15、RANTES、TGF-β1 和 TNF-α 细胞因子的作用，同时恢复 MCP-2 水平，表明 H4K12ac 可能在炎症过程中发挥重要作用，并可能作为慢性酒精条件下的炎症调节剂或细胞应激反应机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/f9c32af3d26e/41598_2017_11172_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/4806d0f869f9/41598_2017_11172_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/248a7a212519/41598_2017_11172_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/d6ec11a59e27/41598_2017_11172_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/f9c32af3d26e/41598_2017_11172_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/4806d0f869f9/41598_2017_11172_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/3df22d60449b/41598_2017_11172_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/ce0a907cc54e/41598_2017_11172_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/248a7a212519/41598_2017_11172_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/d6ec11a59e27/41598_2017_11172_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acaa/5593989/f9c32af3d26e/41598_2017_11172_Fig6_HTML.jpg

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