Inhibition of MicroRNA let-7i Depresses Maturation and Functional State of Dendritic Cells in Response to Lipopolysaccharide Stimulation via Targeting Suppressor of Cytokine Signaling 1
Inhibition of MicroRNA let-7i Depresses Maturation and Functional State of Dendritic Cells in Response to Lipopolysaccharide Stimulation via Targeting Suppressor of Cytokine Signaling 1
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DOI：
10.4049/jimmunol.1001937
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发表时间：
2011-08-15
影响因子：
4.4
通讯作者：
Wu, Jian
中科院分区：
文献类型：
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作者：
Zhang, Maomao;Liu, Fang;Wu, Jian
树突状细胞(DC)可以根据功能状态启动免疫反应或授予免疫耐受性。脂多糖诱导的DC成熟是通过增强CD80和CD86的表面表达来定义的。MicroRNAs在DC功能和免疫调节中起关键作用，在内毒素诱导的DC成熟过程中，microRNA let-7i表达上调。下调let-7i可显著抑制DC的成熟，表现为CD80和CD86的表达减少。在共培养条件下，LPS刺激的DC可促进T细胞的增殖，而下调了let-7i的LPS刺激的DC不能刺激T细胞的增殖，但能促进调节性T细胞(Treg)的扩增。LET-7I表达下调的DC有两个亚群：CD86(-)和CD86(+)，其中CD86(-)DC诱导T细胞低反应性和增强Treg细胞数的作用更强，表明该DC具有耐受性。此外，上调IL-10的树突状细胞强调了CD86(-)DC的耐受作用。细胞因子信号转导抑制因子1(SOCS1)是DC成熟的重要调节因子，荧光素酶构建实验证实其为let-7I靶基因。抑制或过表达let-7i可引起SOCS1蛋白表达的双向改变，但对SOCS1的mRNA水平无显著影响，提示let-7i通过翻译抑制调节SOCS1的表达。LET-7i对SOCS1蛋白的调节主要限于CD86(-)DC。我们的研究表明，let-7i对SOCS1的调节对内毒素诱导的DC成熟和免疫功能至关重要。动态调节let-7i可能通过诱导抗原特异性免疫耐受来微调免疫反应。免疫学杂志，2011,187：1674-1683。
Dendritic cells (DCs) can initiate immune responses or confer immune tolerance depending on functional status. LPS-induced DC maturation is defined by enhanced surface expression of CD80 and CD86. MicroRNAs are critical for the regulation of DC function and immunity, and the microRNA let-7i was upregulated during LPS-induced DC maturation. Downregulation of let-7i significantly impeded DC maturation as evidenced by reduced CD80 and CD86 expression. DCs stimulated by LPS promoted T cell proliferation in coculture, whereas LPS-stimulated DCs with downregulated let-7i were not effective at stimulating T cell proliferation but promoted expansion of the regulatory T cell (Treg) population. There were two subpopulations of LPS-stimulated DCs with downregulated let-7i, CD86(-) and CD86(+), and it was the CD86(-) DCs that were more effective in inducing T cell hyporesponsiveness and enhancing Treg numbers, indicating that this DC population had tolerogenic properties. Furthermore, Tregs with upregulated IL-10 underscored the tolerogenic effect of CD86(-) DCs. Suppressor of cytokine signaling 1 (SOCS1), a crucial mediator of DC maturation, was confirmed as a let-7i target gene by luciferase construct assay. Suppression or overexpression of let-7i caused reciprocal alterations in SOCS1 protein expression, but had no significant effects on SOCS1 mRNA levels, indicating that let-7i regulated SOCS1 expression by translational suppression. The modulation of SOCS1 protein by let-7i was mainly restricted to CD86(-) DCs. Our study demonstrates that let-7i regulation of SOCS1 is critical for LPS-induced DC maturation and immune function. Dynamic regulation of let-7i may fine-tune immune responses by inducing Ag-specific immune tolerance. The Journal of Immunology, 2011, 187: 1674-1683.