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首页> 美国卫生研究院文献>Oncotarget >α7 nAChR mediated Fas demethylation contributes to prenatal nicotine exposure-induced programmed thymocyte apoptosis in mice
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α7 nAChR mediated Fas demethylation contributes to prenatal nicotine exposure-induced programmed thymocyte apoptosis in mice

机译：α7nAChR介导的Fas去甲基化有助于小鼠产前尼古丁暴露引起的程序性胸腺细胞凋亡

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This study aimed to investigate the effects of prenatal nicotine exposure (PNE) on thymocyte apoptosis and postnatal immune impairments in vivo and further explore the epigenetic mechanisms of the pro-apoptotic effect of nicotine in vitro. The results showed that PNE caused immune impairments in offspring on postnatal day 49, manifested as increased IL-4 production and an increased IgG1/IgG2a ratio in serum. Enhanced apoptosis of total and CD4+SP thymocytes was observed both in fetus and in offspring. Further, by exposing thymocytes to 0–100 μM of nicotine in vitro for 48 h, we found that nicotine increased α7 nicotinic acetylcholine receptor (nAChR) expression, activated the Fas apoptotic pathway, and promoted thymocyte apoptosis in concentration-dependent manners. In addition, nicotine could induce Tet methylcytosine dioxygenase (TET) 2 expression and Fas promoter demethylation, which can be abolished by TET2 siRNA transfection. Moreover, the α7 nAChR specific antagonist α-bungarotoxin can abrogate nicotine-induced TET2 increase, and the following Fas demethylation and Fas-mediated apoptosis. In conclusion, our findings showed, for the first time, that α7 nAChR activation could induce TET2-mediated Fas demethylation in thymocytes and results in the upregulation of Fas apoptotic pathway, which provide evidence for elucidating the PNE-induced programmed thymocyte apoptosis.
机译：这项研究旨在调查产前烟碱暴露（PNE）对体内胸腺细胞凋亡和产后免疫损伤的影响，并进一步探讨烟碱促凋亡作用的表观遗传机制。结果表明，PNE在出生后第49天导致后代免疫受损，表现为IL-4产生增加和血清IgG1 / IgG2a比增加。在胎儿和后代中均观察到总胸腺和CD4 + SP胸腺细胞的凋亡增强。此外，通过在体外将胸腺细胞暴露于0–100μM尼古丁中48 h，我们发现尼古丁以浓度依赖的方式增加了α7烟碱型乙酰胆碱受体（nAChR）的表达，激活了Fas凋亡途径，并促进了胸腺细胞凋亡。此外，尼古丁可以诱导Tet甲基胞嘧啶双加氧酶（TET）2表达和Fas启动子去甲基化，这可以通过TET2 siRNA转染来消除。此外，α7nAChR特异性拮抗剂α-真菌毒素可以消除烟碱诱导的TET2升高，以及随后的Fas去甲基化和Fas介导的细胞凋亡。总之，我们的发现首次表明，α7nAChR激活可以诱导TET2介导的胸腺细胞Fas去甲基化，并导致Fas凋亡途径上调，这为阐明PNE诱导的程序性胸腺细胞凋亡提供了证据。

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