Compared to females, males are more susceptible to acute viral and other respiratory tract infections that display greater severity and higher mortality. In contrast, females tend to fare worse with chronic inflammatory diseases. Circulating 17β-estradiol (E2) is a female-specific factor that may influence the progression of human lung diseases. Here we hypothesize that E2 modulates the inflammatory response of monocytes through microRNA (miRNA)-based modulation of secretory leucoprotease inhibitor (SLPI), an antiprotease with immunomodulatory effects. Monocytic cells were treated ± E2, and differentially expressed miRNAs were identified using PCR profiling. Cells were transfected with miRNA mimics or antimiRs and SLPI mRNA and protein levels were quantified. Luciferase activity assay using wildtype and ΔmiR-19a/b-SLPI3'UTR reporter constructs and chromatin immunoprecipitation on E2-treated monocytes were performed. E2 downregulated SLPI and upregulated miR-19 expression in monocytes. Transfection with premiR-19b reduced SLPI mRNA and protein levels and this effect was abrogated using antimiRs against miR-19b. miR-19b directly binds the SLPI 3'UTR. The mechanism responsible for E2-mediated upregulation of miR-19 occurs via increased MIR17HG promoter activity mediated by c-MYC. Overall E2 decreases SLPI expression in human monocytic cells, via changes in miRNA expression and highlights the potential for estrogen to modulate the innate immune system.

中文翻译：

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雌激素诱导的miR-19下调单核细胞中分泌型白蛋白蛋白酶抑制剂的表达。

与女性相比，男性更容易受到急性病毒感染和其他呼吸道感染的感染，表现出更高的严重性和更高的死亡率。相反，女性在慢性炎症性疾病中的病情更糟。循环中的17β-雌二醇（E2）是女性特有的因子，可能会影响人类肺部疾病的进展。在这里，我们假设E2通过分泌性白蛋白蛋白酶抑制剂（SLPI）的基于microRNA（miRNA）的调节来调节单核细胞的炎症反应，这是一种具有免疫调节作用的抗蛋白酶。将单核细胞处理为±E2，并使用PCR谱分析鉴定差异表达的miRNA。用miRNA模拟物或antimiRs转染细胞，并定量SLPI mRNA和蛋白质水平。使用野生型和ΔmiR-19a/ b-SLPI3'的萤光素酶活性测定 在E2处理的单核细胞上进行了UTR报告基因构建和染色质免疫沉淀。E2下调单核细胞中的SLPI和上调miR-19的表达。使用premiR-19b转染可降低SLPI mRNA和蛋白水平，使用针对miR-19b的antimiR可以消除这种作用。miR-19b直接结合SLPI 3'UTR。负责E2介导的miR-19上调的机制是通过c-MYC介导的MIR17HG启动子活性增加而发生的。总体E2会通过miRNA表达的变化降低人单核细胞中SLPI的表达，并强调雌激素调节先天免疫系统的潜力。使用premiR-19b转染可降低SLPI mRNA和蛋白水平，使用针对miR-19b的antimiR可以消除这种作用。miR-19b直接结合SLPI 3'UTR。负责E2介导的miR-19上调的机制是通过c-MYC介导的MIR17HG启动子活性增加而发生的。总体E2会通过miRNA表达的变化降低人单核细胞中SLPI的表达，并强调雌激素调节先天免疫系统的潜力。使用premiR-19b转染可降低SLPI mRNA和蛋白水平，使用针对miR-19b的antimiR可以消除这种作用。miR-19b直接结合SLPI 3'UTR。负责E2介导的miR-19上调的机制是通过c-MYC介导的MIR17HG启动子活性增加而发生的。总体E2会通过miRNA表达的变化降低人单核细胞中SLPI的表达，并强调雌激素调节先天免疫系统的潜力。