Histone deacetylases inhibit IFN-gamma-inducible gene expression in mouse trophoblast cells.
Histone deacetylases inhibit IFN-gamma-inducible gene expression in mouse trophoblast cells.
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DOI：
10.4049/jimmunol.0802454
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发表时间：
2009-05-15
期刊：
影响因子：
--
通讯作者：
Murphy SP
中科院分区：
文献类型：
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作者：
Choi JC;Holtz R;Murphy SP
滋养层细胞是从发育中的哺乳动物胚胎中分化出来的第一批细胞，它们随后形成胎盘的胚泡衍生成分。IFN-γ在激活先天性和适应性免疫以及细胞凋亡中起关键作用。在小鼠中，IFN-γ在妊娠子宫中产生，并且对于胎盘的蜕膜层的形成和子宫脉管系统的重塑是必需的。小鼠滋养层细胞对IFN-γ的反应似乎是选择性的，因为IFN-γ激活MHC I类表达并增强吞噬作用，但不能激活这些细胞中的MHC II类表达或凋亡。为了研究小鼠滋养层细胞选择性IFN-γ应答的分子基础，在滋养层细胞系SM 9和M-11、滋养层干细胞和滋养层干细胞衍生的巨细胞中检测IFN-γ诱导的基因表达。与成纤维细胞相比，滋养层细胞中IFN-γ诱导的多个基因（包括IFN调节因子-1（IRF-1）的表达显著降低。滋养层细胞中IRF-1 mRNA表达降低是由于IRF-1转录速率相对于成纤维细胞降低。然而，在IFN-γ处理的小鼠滋养层细胞中没有观察到STAT-1酪氨酸磷酸化或DNA结合能力的损害。重要的是，组蛋白去乙酰化酶（HDAC）抑制剂显著增强滋养层细胞中IFN-γ诱导的基因表达，但不是成纤维细胞。我们的集体研究表明，IFN-γ诱导的基因表达在小鼠滋养层细胞中被HDAC抑制。我们认为HDAC介导的小鼠滋养层细胞中IFN-γ诱导基因表达的抑制可能有助于成功妊娠，因为它可以阻止IFN-γ反应的激活，否则可能会促进胎盘的破坏。
Trophoblast cells are the first cells to differentiate from the developing mammalian embryo, and they subsequently form the blastocyst-derived component of the placenta. IFN-γ plays critical roles in activating innate and adaptive immunity, as well as apoptosis. In mice, IFN-γ is produced in the pregnant uterus, and is essential for formation of the decidual layer of the placenta and remodeling of the uterine vasculature. Responses of mouse trophoblast cells to IFN-γ appear to be selective, for IFN-γ activates MHC class I expression and enhances phagocytosis, but fails to activate either MHC class II expression or apoptosis in these cells. To investigate the molecular basis for the selective IFN-γ responsiveness of mouse trophoblast cells, IFN-γ-inducible gene expression was examined in the trophoblast cell lines SM9 and M-11, trophoblast stem cells, and trophoblast stem cell-derived giant cells. IFN-γ-inducible expression of multiple genes, including IFN regulatory factor-1 (IRF-1), was significantly reduced in trophoblast cells compared with fibroblast cells. Decreased IRF-1 mRNA expression in trophoblast cells was due to a reduced rate of IRF-1 transcription relative to fibroblast cells. However, no impairment of STAT-1 tyrosine phosphorylation or DNA-binding capacity was observed in IFN-γ-treated mouse trophoblast cells. Importantly, histone deacetylase (HDAC) inhibitors significantly enhanced IFN-γ-inducible gene expression in trophoblast cells, but not fibroblasts. Our collective studies demonstrate that IFN-γ-inducible gene expression is repressed in mouse trophoblast cells by HDACs. We propose that HDAC-mediated inhibition of IFN-γ-inducible gene expression in mouse trophoblast cells may contribute to successful pregnancy by preventing activation of IFN-γ responses that might otherwise facilitate the destruction of the placenta.