Knockdown of MicroRNA-155 in Kupffer Cells Results in Immunosuppressive Effects and Prolongs Survival of Mouse Liver Allografts
Knockdown of MicroRNA-155 in Kupffer Cells Results in Immunosuppressive Effects and Prolongs Survival of Mouse Liver Allografts
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Kupffer 细胞中 microRNA-155 的敲低导致免疫抑制作用并延长小鼠同种异体肝脏移植物的存活
DOI：
10.1097/tp.0000000000000061
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发表时间：
2014-03-27
期刊：
影响因子：
6.2
通讯作者：
Gong, Jianping
中科院分区：
文献类型：
--
作者：
Li, Jinzheng;Gong, Junhua;Gong, Jianping
背景：我们以往的研究表明，Kupffer细胞(KCs)在术后的病理变化中起着至关重要的作用。最近的报道表明，microRNA-155(miR-155)与移植患者外周血和同种异体移植物中的炎症和促炎介质的上调有关。方法分离BALB/c小鼠KCs，分别用miR-155模拟物或抑制剂转染KCs。检测细胞因子信号转导和转录激活因子(SOCS1/JAK/STAT)蛋白和表面分子(MHC-II、CD40、CD86)水平。混合淋巴细胞反应检测T细胞增殖和凋亡情况。结果miR-155基因敲除KCs后，MHC-II、CD40、CD86的表达下降，抗原提呈功能受到抑制，SOCS1/JAK/STAT炎症通路受到影响。此外，转染miR-155抑制剂的KCs与T淋巴细胞共培养后，T细胞应答降低，但出现更多的T细胞凋亡。最后，抑制移植肝中miR-155可延长移植肝存活时间并改善肝功能。这些变化与T辅助细胞1和2(Th1/Th2)细胞因子水平和T细胞凋亡密切相关，但体内机制尚未建立直接联系。结论miR-155调节小鼠Th1/Th2细胞因子平衡和KCs的成熟和功能。KCs中的MIR-155抑制正向调节KC的免疫抑制功能，延长肝移植存活时间。
Background Our previous studies have shown that Kupffer cells (KCs) play a crucial role in postoperative pathologic changes. Recent reports have demonstrated that microRNA-155 (miR-155) is associated with inflammation and upregulation of proinflammatory mediators in the peripheral blood and allografts of transplant patients. However, the precise mechanism for this remains unknown.Methods KCs isolated from BALB/c mice were transfected with miR-155 mimic or inhibitor. Levels of suppressor of cytokine signaling 1/Janus kinase/signal transducer and activator of transcription (SOCS1/JAK/STAT) proteins and surface molecules (MHC-II, CD40, and CD86) were then measured. T-cell proliferation and apoptosis were evaluated in mixed lymphocyte reactions. Orthotopic liver transplantation was performed in mice after miR-155 short hairpin RNA lentivirus treatment, and postoperative survival, liver function and histology, and mRNA and protein expression were analyzed.Results miR-155 knockdown in KCs decreased MHC-II, CD40, and CD86 expression, suppressed antigen-presenting function, and affected SOCS1/JAK/STAT inflammatory pathways. In addition, KCs transfected with miR-155 inhibitor and cocultured with T lymphocytes showed reduced T-cell responses but a greater number of apoptotic T cells. Finally, miR-155 suppression in graft liver prolonged liver allograft survival and improved liver function. The changes were closely associated with the levels of T helper 1 and 2 (Th1/Th2) cytokines and T-cell apoptosis, but a direct mechanistic link in vivo was not established.Conclusion These data suggest miR-155 regulates the balance of Th1/Th2 cytokines and the maturation and function of KCs in mice. miR-155 repression in KCs positively regulates KC function toward immunosuppression and prolongs liver allograft survival.