Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses.
Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses.
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DOI：
10.4049/jimmunol.1301758
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发表时间：
2014-03-01
期刊：
影响因子：
--
通讯作者：
Monick MM
中科院分区：
文献类型：
--
作者：
Gross TJ;Kremens K;Powers LS;Brink B;Knutson T;Domann FE;Philibert RA;Milhem MM;Monick MM
巨噬细胞，包括肺泡巨噬细胞，是先天免疫系统的主要吞噬细胞。巨噬细胞和炎症的许多研究已经在小鼠模型中完成，其中诱导型一氧化氮合酶（NOS 2）和一氧化氮（NO）是炎症反应的重要组成部分。与小鼠巨噬细胞相反，人类巨噬细胞表达很少可检测的NOS2，并且响应于强有力的炎症刺激产生很少的NO。人NOS2基因在NOS2转录起始位点周围高度甲基化。相比之下，小鼠巨噬细胞含有未甲基化的胞嘧啶磷酸鸟嘌呤二核苷酸（CpG）接近的NOS2转录起始位点。染色质可及性和组蛋白修饰的进一步分析表明，在人NOS2基因座的封闭构象和在小鼠NOS2基因座的开放构象。在研究NOS2位点CpG去甲基化的潜力时，我们发现人NOS2基因在体外和体内都对去甲基化剂的作用具有抗性。我们的数据表明，人类巨噬细胞中的表观遗传修饰与CpG甲基化、染色质致密化和组蛋白修饰相关，这些修饰有效地沉默了NOS2基因。总之，我们的研究结果表明，在小鼠和人类巨噬细胞对炎症刺激的反应方面存在显着且未被充分认识的差异。
Macrophages, including alveolar macrophages, are primary phagocytic cells of the innate immune system. Many studies of macrophages and inflammation have been done in mouse models, where inducible nitric oxide synthase (NOS2) and nitric oxide (NO) are important components of the inflammatory response. Human macrophages, in contrast to mouse macrophages, express little detectable NOS2 and generate little NO in response to potent inflammatory stimuli. The human NOS2 gene is highly methylated around the NOS2 transcription start site. In contrast, mouse macrophages contain unmethylated cytosine-phosphate-guanine dinucleotides (CpGs) proximal to the NOS2 transcription start site. Further analysis of chromatin accessibility and histone modifications demonstrated a closed conformation at the human NOS2 locus and an open conformation at the murine NOS2 locus. In examining the potential for CpG demethylation at the NOS2 locus, we found that the human NOS2 gene was resistant to the effects of demethylation agents both in vitro and in vivo. Our data demonstrates that epigenetic modifications in human macrophages are associated with CpG methylation, chromatin compaction and histone modifications that effectively silence the NOS2 gene. Taken together, our findings suggest there are significant and under-appreciated differences in how murine and human macrophages respond to inflammatory stimuli.
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