Van Twisk Daniel, Murphy Shawn P, Thakar Juilee
Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA.
Department of Obstetrics and Gynecology, University of Rochester, Rochester, NY, USA.
Immunology. 2017 May;151(1):71-80. doi: 10.1111/imm.12707. Epub 2017 Feb 9.
The pro-inflammatory cytokine interferon-γ (IFN-γ) is critical for activating innate and adaptive immunity against tumours and intracellular pathogens. Interferon-γ is secreted at the fetal-maternal interface in pregnant women and mice. The outer layer of the placenta in contact with maternal blood is composed of semi-allogeneic trophoblast cells, which constitute the fetal component of the fetal-maternal interface. The simultaneous presence of pro-inflammatory IFN-γ and trophoblast cells at the fetal-maternal interface appears to represent an immunological paradox, for trophoblastic responses to IFN-γ could potentially lead to activation of maternal immunity and subsequent attack of the placenta. However, our previous studies demonstrate that IFN-γ responsive gene (IRG) expression is negatively regulated in human and mouse trophoblast cells. In human cytotrophoblast and trophoblast-derived choriocarcinoma cells, janus kinase signalling is blocked by protein tyrosine phosphatases (PTPs), whereas in mouse trophoblast, histone deacetylases (HDACs) inhibit IRG expression. Here, we used genome-wide transcriptional profiling to investigate the collective roles of PTPs and HDACs on regulation of IRG expression in human choriocarcinoma cells. Logic-rules were optimized to derive regulatory modes governing gene expression patterns observed upon different combinations of treatment with PTP and HDAC inhibitors. The results demonstrate that IRGs can be divided into several categories in human choriocarcinoma cells, each of which is subject to distinct mechanisms of repression. Hence, the regulatory modes identified in this study suggest that human trophoblast and choriocarcinoma cells may evade the potentially deleterious consequences of exposure to IFN-γ by using several overlapping mechanisms to block IRG expression.
促炎细胞因子干扰素-γ（IFN-γ）对于激活针对肿瘤和细胞内病原体的先天性和适应性免疫至关重要。在孕妇和小鼠的母胎界面处会分泌干扰素-γ。与母体血液接触的胎盘外层由半同种异体滋养层细胞组成，这些细胞构成了母胎界面的胎儿部分。在母胎界面同时存在促炎的IFN-γ和滋养层细胞似乎代表了一种免疫学上的矛盾现象，因为滋养层细胞对IFN-γ的反应可能会激活母体免疫并随后攻击胎盘。然而，我们之前的研究表明，IFN-γ反应基因（IRG）的表达在人和小鼠的滋养层细胞中受到负调控。在人细胞滋养层细胞和滋养层来源的绒毛膜癌细胞中，蛋白酪氨酸磷酸酶（PTP）会阻断janus激酶信号传导，而在小鼠滋养层细胞中，组蛋白脱乙酰酶（HDAC）会抑制IRG的表达。在这里，我们使用全基因组转录谱分析来研究PTP和HDAC对人绒毛膜癌细胞中IRG表达调控的共同作用。对逻辑规则进行了优化，以推导在使用PTP和HDAC抑制剂进行不同组合处理时观察到的基因表达模式的调控模式。结果表明，在人绒毛膜癌细胞中IRG可分为几类，每一类都受到不同的抑制机制的影响。因此，本研究中确定的调控模式表明，人滋养层细胞和绒毛膜癌细胞可能通过使用几种重叠机制来阻断IRG表达，从而规避暴露于IFN-γ可能带来的有害后果。
