miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1
miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1
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DOI：
10.1182/blood-2010-12-322503
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发表时间：
2011-04-21
期刊：
影响因子：
20.3
通讯作者：
Zhou, Xianzheng
中科院分区：
文献类型：
--
作者：
Lu, Changming;Huang, Xin;Zhou, Xianzheng
树突状细胞（Dendritic cells，DC）是来源于造血祖细胞和循环单核细胞的有效抗原呈递细胞。为了研究微小RNA（miRNA）在DC分化、成熟和功能中的作用，我们分析了人单核细胞、未成熟DC（imDC）和成熟DC（mDC）中的miRNA表达。在单核细胞分化为imDCs和mDCs的过程中，发现了27种miRNA的阶段特异性差异表达。其中，miR-221表达减少和miR-155表达增加与DC中p27（kip 1）积累相关。miR-221沉默或miR-155过表达可导致p27（kip 1）蛋白表达增加和DC凋亡。此外，来自miR-155（-/-）小鼠的mDC比来自野生型小鼠的mDC凋亡更少。miR-155表达沉默对DC成熟影响不大，但减少了IL-12 p70的产生，而miR-155过表达则增加了mDC的IL-12 p70产生。Kip 1泛素化促进复合物1、细胞因子信号转导抑制因子1和CD 115（M-CSFR）是miR-155的功能靶点。此外，我们提供的证据表明，miR-155通过靶向Kip 1泛素化促进复合物1间接调节p27（kip 1）蛋白水平。因此，我们的研究揭示了单核细胞分化为DC过程中的miRNA特征以及miR-221和miR-155在DC凋亡和IL-12 p70产生中的新调节作用。（血。2011; 117（16）：4293-4303）
Dendritic cells (DCs) are potent antigen-presenting cells derived from hematopoietic progenitor cells and circulating monocytes. To investigate the role of microRNAs (miRNAs) during DC differentiation, maturation, and function, we profiled miRNA expression in human monocytes, immature DCs (imDCs), and mature DCs (mDCs). Stage-specific, differential expression of 27 miRNAs was found during monocyte differentiation into imDCs and mDCs. Among them, decreased miR-221 and increased miR-155 expression correlated with p27(kip1) accumulation in DCs. Silencing of miR-221 or overexpressing of miR-155 in DCs resulted in p27(kip1) protein increase and DC apoptosis. Moreover, mDCs from miR-155(-/-) mice were less apoptotic than those from wild-type mice. Silencing of miR-155 expression had little effect on DC maturation but reduced IL-12p70 production, whereas miR-155 overexpression inmDCsenhanced IL-12p70 production. Kip1 ubiquitination-promoting complex 1, suppressor of cytokine signaling 1, and CD115 (M-CSFR) were functional targets of miR-155. Furthermore, we provide evidence that miR-155 indirectly regulated p27(kip1) protein level by targeting Kip1 ubiquitination-promoting complex 1. Thus, our study uncovered miRNA signatures during monocyte differentiation into DCs and the new regulatory role of miR-221 and miR-155 in DC apoptosis and IL-12p70 production. (Blood. 2011; 117(16):4293-4303)