Oncotarget

Research Papers:

α7 nAChR mediated Fas demethylation contributes to prenatal nicotine exposure-induced programmed thymocyte apoptosis in mice

Han-Xiao Liu, Sha Liu, Wen Qu, Hui-Yi Yan, Xiao Wen, Ting Chen, Li-Fang Hou and Jie Ping _

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Oncotarget. 2017; 8:93741-93756. https://doi.org/10.18632/oncotarget.21526

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Abstract

Han-Xiao Liu1, Sha Liu1, Wen Qu1, Hui-Yi Yan1, Xiao Wen1, Ting Chen1, Li-Fang Hou1 and Jie Ping1

1Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China

Correspondence to:

Jie Ping, email: pingjie@whu.edu.cn

Keywords: prenatal nicotine exposure, α7 nAChR, thymocyte apoptosis, TET2, Fas promoter demethylation

Received: July 03, 2017     Accepted: September 20, 2017     Published: October 05, 2017

ABSTRACT

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.


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