Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
Tianjin General Surgery Institute, Tianjin, China.
J Transl Med. 2018 Mar 20;16(1):71. doi: 10.1186/s12967-018-1441-7.
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) characterized by chronic inflammation of colon. It is commonly believed that the imbalance of immune system and overwhelming production of cytokines are involved in the pathogenesis of UC. Recent studies demonstrated that interleukin-35 (IL-35), a key player in the regulation of inflammation, has been identified as potential therapeutic target to treat UC. However, conventional intravenous administration is costly and inconvenient. The present study was designed to establish a novel IL-35 delivery system and investigate its therapeutic effects on dextran sulfate sodium (DSS)-induced experimental colitis in mice for the first time.
An engineered Escherichia coli (E. coli/IL-35) expressing IL-35 was constructed. Adult male BALB/c mice randomly got the oral administration of E. coli/IL-35, empty plasmid-transformed E. coli (E. coli0) or PBS for treatment following ingestion of 3% DSS solution for 5 days. Normal mice were used as control group. Colonic and splenic tissues were collected on day 10 post-DSS-induction. Clinical signs, disease activity index (DAI), pathological and immunohistological changes, cytokine profiles and cell populations were evaluated.
Intragastric administration of E. coli/IL-35 effectively protected the colitis mice from DSS assimilation including weight loss and colon shortening. Pathological analysis showed significantly lower DAI score and much less intra-colon infiltration of neutrophils and CD3 cells in the IL-35 treated group. Moreover, E. coli/IL-35-treated mice demonstrated much less CD4 IL-17A Th17 cells and a higher level of CD4CD25Foxp3 Tregs in spleen and mesenteric lymph nodes, as well as increased colon and serum level of IL-10 and IL-35 and decreased levels of IL-6.
Our study showed that E. coli/IL-35 as a novel oral IL-35 delivery system alleviated inflammatory damage of colonic tissue in the colitic mice. Genetic therapeutic strategies using engineered E. coli encoding immunoregulatory cytokines may provide a potential approach for the treatment of IBD.
溃疡性结肠炎（UC）是一种炎症性肠病（IBD），其特征为结肠慢性炎症。目前普遍认为，免疫系统失衡和细胞因子过度产生与 UC 的发病机制有关。最近的研究表明，白细胞介素-35（IL-35），一种调节炎症的关键因子，已被确定为治疗 UC 的潜在治疗靶点。然而，传统的静脉给药既昂贵又不方便。本研究首次设计了一种新型 IL-35 递药系统，并研究了其在葡聚糖硫酸钠（DSS）诱导的实验性结肠炎小鼠模型中的治疗效果。
构建了表达 IL-35 的工程大肠杆菌（E. coli/IL-35）。成年雄性 BALB/c 小鼠在摄入 3% DSS 溶液 5 天后，随机接受 E. coli/IL-35、空载质粒转化的大肠杆菌（E. coli0）或 PBS 口服治疗。正常小鼠作为对照组。在 DSS 诱导后第 10 天收集结肠和脾组织。评估临床症状、疾病活动指数（DAI）、组织病理学和免疫组织化学变化、细胞因子谱和细胞群。
E. coli/IL-35 灌胃给药可有效保护结肠炎小鼠免受 DSS 同化，包括体重减轻和结肠缩短。组织学分析显示，IL-35 治疗组小鼠的 DAI 评分明显较低，结肠内中性粒细胞和 CD3 细胞浸润明显减少。此外，E. coli/IL-35 治疗组小鼠的脾和肠系膜淋巴结中 CD4IL-17A Th17 细胞减少，CD4CD25Foxp3 Treg 细胞增多，结肠和血清中 IL-10 和 IL-35 水平升高，IL-6 水平降低。
本研究表明，E. coli/IL-35 作为一种新型口服 IL-35 递药系统，可减轻结肠炎小鼠结肠组织的炎症损伤。利用工程大肠杆菌表达免疫调节细胞因子的基因治疗策略可能为 IBD 的治疗提供一种新方法。
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