Butyrate suppresses murine mast cell proliferation and cytokine production through inhibiting histone deacetylase.
Butyrate suppresses murine mast cell proliferation and cytokine production through inhibiting histone deacetylase.
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DOI：
10.1016/j.jnutbio.2015.09.020
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Hanying Zhang;M. Du;Qiyuan Yang;Mei-Jun Zhu
中科院分区：
文献类型：
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作者：
Hanying Zhang;M. Du;Qiyuan Yang;Mei-Jun Zhu
除了对结肠上皮细胞的营养影响外，肠道微生物群代谢物丁酸盐对宿主细胞具有多效性作用，并且已知其对肠道稳态和代谢的有益作用。然而，它如何调节肥大细胞功能仍不清楚。在这里，我们表明，丁酸酯通过诱导细胞周期阻滞和凋亡，以及减少c-Kit激活，深刻地抑制小鼠肥大细胞瘤P815细胞的增殖。此外，丁酸增加早期和晚期凋亡的P815细胞。在小鼠骨髓源性肥大细胞（BMMC）中，丁酸盐抑制Fc ε RI依赖性肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）的释放，而不影响β-氨基己糖苷酶，但这与丝裂原活化蛋白激酶细胞外信号调节激酶1/2、p38和c-Jun N-末端激酶活化降低有关。丁酸盐处理显著增强了P815和BMMC中组蛋白3的乙酰化，并降低了BMMC中TNF-α andil-6的Fc ε RI依赖性mRNA表达，模拟了已知的组蛋白去乙酰化酶抑制剂曲古抑菌素A的作用。染色质免疫沉淀显示丁酸盐增强了TNF-α andil-6基因启动子区域的乙酰化，但阻断了RNA聚合酶II与TNF-α andil-6基因启动子的结合，表明丁酸盐抑制了转录起始。这些表型模拟曲古抑菌素A治疗的那些。总之，丁酸盐抑制肥大细胞瘤P815细胞的细胞增殖并增加细胞凋亡，并抑制小鼠原代BMMC中Fc ε RI依赖性细胞因子的产生，这可能是由HDAC抑制介导的。
Beyond their nutritional impact to colonic epithelial cells, the intestinal microbiota metabolite butyrate has pleotropic effects to host cells and is known for its beneficial effects on intestinal homeostasis and metabolism. However, it remains unclear how it modulates mast cell function. Here, we demonstrate that butyrate profoundly inhibited proliferation of mouse mastocytoma P815 cells through inducing cell cycle arrest and apoptosis, as well as decreasing c-Kit activation. In addition, butyrate increased early- and late-stage apoptotic P815 cells. In murine bone marrow-derived mast cells (BMMC), butyrate-suppressed FcεRI-dependent tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) release without affecting β-Hexosaminidase, but that was associated with decreased mitogen-activated protein kinase extracellular signal-regulated kinase 1/2, p38 and c-Jun N-terminal kinases activation. Butyrate treatment substantially enhanced histone 3 acetylation in both P815 and BMMC and decreased FcεRI-dependent mRNA expression oftnf-αandil-6in BMMC, mimicking the effect of Trichostatin A, a known histone deacetylase inhibitor. Chromatin immunoprecipitation revealed that butyrate enhanced acetylation of thetnf-αandil-6promoter regions but blocked RNA polymerase II binding to the promoters oftnf-αandil-6genes, indicating suppressed transcription initiation. These phenotypes mimicked those of Trichostatin A treatment. In conclusion, butyrate inhibits cell proliferation and increases cell apoptosis in mastocytoma P815 cells and suppresses FcεRI-dependent cytokine production in murine primary BMMC, which are likely mediated by HDAC inhibition.