miR-145促进天然免疫应答中巨噬细胞产生白细胞介素10及其表观遗传机制研究

发布时间：2018-05-19 10:44

本文选题：microRNA + IL-10　；参考：《浙江大学》2011年博士论文

【摘要】：抑炎性细胞因子白血病介素10(IL-10)的表达在免疫调节中发挥重要作用,其表达调控方式和相关机制目前受广泛关注。尽管在信号转导、转录调控和表观修饰等调控IL-10表达方面已有较多报道,但目前有关microRNA调控IL-10表达的研究报道却知之甚少。microRNA为近年来发现的一类小分子非编码RNA,它在包括免疫应答在内的许多生物学过程中均发挥重要的调控功能。本研究中,我们通过VSV病毒感染小鼠腹腔巨噬细胞前后的高通量miRNA芯片筛选,发现VSV感染后胞内miR。145/miR-143的表达水平发生显著下调。进一步研究揭示TLRs及RIG-I信号活化所诱导的miR-145/miR-143表达下调依赖于天然免疫细胞I型干扰素的表达及其下游信号途径的活化。miR-145的功能研究提示其可以增强LPS诱导的巨噬细胞Il10转录活化,上调IL-10的表达,进而间接抑制IL-12 p70的产生。由于miRNA主要通过调控其靶基因的表达进而发挥生物学功能,进一步的机制研究阐明miR-145可以靶向抑制HDAC11的表达,而HDAC11为可促Il10基因沉默的表观调控蛋白。因此,本研究结果显示, miR-145可通过在转录后水平抑制表观调控蛋白HDAC11,从而上调天然免疫细胞活化后IL-10的表达,进而调控免疫应答处于适度状态。该结果对于天然免疫应答中抑炎因子IL-10表达的调控提出了新的机制。
[Abstract]:The expression of interleukin-10 (IL-10) plays an important role in the immunomodulation of inflammatory cytokine leukemia. Although there have been many reports on the regulation of IL-10 expression in signal transduction, transcriptional regulation and epidermal modification, However, little is known about the regulation of IL-10 expression by microRNA. MicroRNAs are a class of small molecule noncoding RNAs, which play an important role in many biological processes, including immune response. In this study, we screened the high-throughput miRNA microarray before and after VSV virus infection in murine peritoneal macrophages, and found that the expression of miR.145/miR-143 in mouse peritoneal macrophages was significantly down-regulated after VSV infection. Further studies revealed that the down-regulation of miR-145/miR-143 expression induced by TLRs and RIG-I signal activation depends on the expression of interferon type I in innate immune cells and the activation of downstream signaling pathway. MiR-145 may enhance macrophage induced by LPS. Il10 transcriptional activation, The expression of IL-10 was up-regulated, which indirectly inhibited the production of IL-12 p70. Since miRNA mainly regulates the expression of its target gene and then plays a biological function, further studies have shown that miR-145 can specifically inhibit the expression of HDAC11, while HDAC11 is an epiregulatory protein that can promote the silencing of Il10 gene. Therefore, miR-145 can up-regulate the expression of IL-10 after activation of innate immune cells by inhibiting HDAC11 at the post-transcriptional level, and then regulate the immune response in a moderate state. These results provide a new mechanism for regulating the expression of IL-10 in innate immune response.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R392

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