Knockdown of Interleukin-2 by shRNA-Mediated RNA Interference Prolongs Liver Allograft Survival
Knockdown of Interleukin-2 by shRNA-Mediated RNA Interference Prolongs Liver Allograft Survival
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DOI：
10.1016/j.jss.2008.09.019
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发表时间：
2010-03-01
影响因子：
2.2
通讯作者：
Gong, Jian-ping
中科院分区：
文献类型：
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作者：
Chen, Yong;Yan, Tao;Gong, Jian-ping
白细胞介素-2（IL-2）在T细胞活化、扩增和稳态中起核心作用。IL-2生物合成的失败可能在耐受诱导中起关键作用。我们检测了用短发夹状RNA（shRNA）阻断IL-2对大鼠肝移植急性排斥反应的调节作用。为此，我们成功地设计并筛选了一个有效的干扰质粒pIL-2B。pIL-2B转染组IL-2 mRNA表达水平仅为未转染组的1/5。采用刘易斯to BN原位肝移植模型，探讨shRNA对IL-2基因敲减的体内效应。经pIL-2-shRNA处理的受者存活时间（中位存活时间为16 d，范围7-21 d）长于空载体组（11;范围5-13）和生理盐水组（9;范围5-13）（P < 0.05），但低于CsA组（24;范围13-36，P < 0.05）。IL-2-shRNA通过减少肝细胞凋亡和减少移植物中IL-2、肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的细胞因子产生来减轻急性排斥反应。我们的研究结果表明，IL-2靶向RNA干扰的方法可能是潜在的利益，在器官移植。(C)2010年爱思唯尔公司All rights reserved.
Interleukin-2 (IL-2) plays a central role in T-cell activation, expansion, and homeostasis. The failure of IL-2 biosynthesis may play a critical role in tolerance induction. We tested the effect of IL-2 blockade by short hairpin RNA (shRNA) on regulating acute rejection in rat liver transplantation. To this end, we successfully designed and selected an effective interference plasmid, pIL-2B. The IL-2 mRNA expression level in the pIL-2B group was one-fifth of that in the no transfection group. Lewis to BN orthotopic liver transplant model was used to explore the effect of knockdown IL-2 by shRNA in vivo. Recipients treated with pIL-2-shRNA survived longer (median survival time of 16 d range 7-21 d) than those with empty vector (11; range 5-13) or saline (9; range 5-13) (P < 0.05), and was inferior to those with CsA (24; range 13-36, P < 0.05). The IL-2-shRNA attenuated acute rejection with decreased apoptosis of hepatocytes and reduced cytokine production of IL-2, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in the graft. Our results suggest that IL-2 targeting using RNA interference approach may be of potential interest in organ transplantation. (C) 2010 Elsevier Inc. All rights reserved.