A NOVEL INTERLEUKIN-10 DNA MUCOSAL DELIVERY SYSTEM ATTENUATES INTESTINAL INFLAMMATION IN A MOUSE MODEL
A NOVEL INTERLEUKIN-10 DNA MUCOSAL DELIVERY SYSTEM ATTENUATES INTESTINAL INFLAMMATION IN A MOUSE MODEL
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DOI：
10.1177/1721727x1301100308
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发表时间：
2013-09-01
影响因子：
0.7
通讯作者：
LeBlanc, J. G.
中科院分区：
文献类型：
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作者：
Del Carmen, S.;Zurita-Turk, M.;LeBlanc, J. G.
炎症性肠病（IBD）描述了一组以胃肠道炎症为特征的复杂肠道疾病。目前 IBD 的治疗方法包括使用抗炎药物；此外，重组乳酸菌已被用作 IBD 模型中抗炎剂的治疗载体。白细胞介素-10 (IL-10) 是最重要的抗炎细胞因子之一；然而，其口服给药受到限制，因为它在胃肠道中迅速降解，全身治疗会导致不良副作用。在这项研究中，开发了一种工程化的乳酸乳球菌 (L.) 侵入菌株，该菌株产生来自金黄色葡萄球菌的纤连蛋白结合蛋白 A (FnBPA+)，能够直接在真核细胞内递送含有小家鼠 IL-10 (pValac:il-10) 编码 ORF 的真核 DNA 表达载体，并使用体外和体内测定评估其功能。质粒和侵入菌株的功能通过使用细胞培养物的转染和侵入性测定以及通过荧光显微镜在小鼠体内进行证明。与接受不含 pValac:il-10 质粒的乳酸乳球菌 FnBPA+ 的小鼠相比，接受这种新菌株的 TNBS 接种小鼠的大肠损伤评分较低（宏观和微观水平），肝脏微生物易位较低，抗炎/促炎细胞因子比率增加。使用小鼠结肠炎模型证明了这种新型 DNA 递送治疗策略在预防炎症方面的有效性。
Inflammatory bowel diseases (IBD) describe a group of complex intestinal disorders characterized by inflammation in the gastrointestinal tract. Current treatments for IBD include the use of antiinflammatory drugs; furthermore, recombinant lactic acid bacteria have been used as a therapeutic vehicle for anti-inflammatory agents in IBD models. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines; however, its oral administration is limited because it is quickly degraded in the gastrointestinal tract and systemic treatments have led to undesirable side effects. In this study, an engineered invasive strain of Lactococcus (L.) lactis producing Fibronectin Binding Protein A (FnBPA+), from Staphylococcus aureus capable of delivering, directly inside eukaryotic cells, an eukaryotic DNA expression vector containing the ORF coding for IL-10 of Mus musculus (pValac:il-10) was developed and its functionality was evaluated using in vitro and in vivo assays. Functionality of the plasmid and the invasive strain was demonstrated by transfection and invasiveness assays using cell cultures and in vivo in mice by fluorescence microscopy. TNBS inoculated mice that received this novel strain showed lower damage scores in their large intestines (at both macroscopic and microscopic levels), lower microbial translocation to liver, and increased anti-inflammatory/pro-inflammatory cytokine ratios compared to mice that received L. lactis FnBPA+ without the pValac:il-10 plasmid. The effectiveness was demonstrated of this novel DNA delivery therapeutic strategy in the prevention of inflammation using a murine model of colitis.