血清淀粉样蛋白A诱导巨噬细胞促炎基因表达的表观遗传学调控

发布时间：2018-04-24 19:41

  本文选题：血清淀粉样蛋白A + Jmjd3　； 参考：《上海交通大学》2014年硕士论文

【摘要】：血清淀粉样蛋白A，作为一种急性期反应蛋白，在吞噬细胞和滑膜成纤维细胞中具有与细胞因子类似的作用。尽管转录因子如NF-B的活化对SAA诱导促炎基因表达具有重要作用，但在这一过程中，表观遗传学调控机制仍不清楚。本课题研究发现，在SAA刺激后的小鼠骨髓巨噬细胞、腹膜巨噬细胞和小鼠巨噬细胞系RAW264.7中，组蛋白H3K27去甲基化酶Jmjd3显著上调。同时，SAA诱导Jmjd3表达伴随着细胞内组蛋白H3K27me3表达水平的下调。在小鼠巨噬细胞系RAW264.7中，当Jmjd3基因被沉默或过表达无活性的Jmjd3突变蛋白时，SAA诱导促炎基因如IL-23p19, G-CSF, TREM-1等表达过程受到明显抑制，并伴随着启动子区H3K27me3甲基化水平的上调。此外，小鼠体内实验进一步证明Jmjd3基因沉默可抑制SAA诱导腹腔巨噬细胞促炎基因的表达，并下调由SAA引起的中性粒细胞增多。最后，我们还发现Jmjd3在SAA诱导的巨噬细胞泡沫化形成中起到重要作用。总之，本课题阐明了一条依赖于Jmjd3调控的SAA诱导促炎细胞因子表达的信号通路，，并为治疗无菌炎症和动脉粥样硬化症指明了潜在的药物靶点。
[Abstract]:Serum amyloid A, as an acute phase reactive protein, plays a similar role with cytokines in phagocytes and synovial fibroblasts. Although the activation of transcription factors such as NF-B plays an important role in the expression of pro-inflammatory genes induced by SAA, the epigenetic regulation mechanism remains unclear. In this study, we found that histone H3K27 demethylase Jmjd3 was significantly up-regulated in SAA stimulated mouse bone marrow macrophages, peritoneal macrophages and mouse macrophages RAW264.7. At the same time, the expression of Jmjd3 was accompanied by down-regulation of histone H3K27me3 expression. In murine macrophage cell line RAW264.7, when the Jmjd3 gene is silenced or overexpression of inactive Jmjd3 mutant protein, the expression process of proinflammatory genes such as IL-23p19, G-CSF, TREM-1 is significantly inhibited, accompanied by the up-regulation of H3K27me3 methylation in the promoter region. In addition, Jmjd3 gene silencing could inhibit the expression of pro-inflammatory gene in peritoneal macrophages induced by SAA and down-regulate the increase of neutrophil induced by SAA in mice. Finally, we found that Jmjd3 plays an important role in the formation of macrophage foam induced by SAA. In conclusion, this study elucidates a signal pathway of pro-inflammatory cytokine expression induced by SAA, which is dependent on the regulation of Jmjd3, and identifies potential drug targets for the treatment of aseptic inflammation and atherosclerosis.
【学位授予单位】：上海交通大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

【共引文献】

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本文编号：1797956