State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
Department of Pharmacy, Fourth People's Hospital of Maanshan, Maanshan, Anhui 243031, P.R. ChinaV.
Int J Mol Med. 2019 Jun;43(6):2291-2302. doi: 10.3892/ijmm.2019.4156. Epub 2019 Apr 4.
The main aim of the present study was to investigate the dual roles and mechanism of interleukin (IL)‑18 in dextran sulfate sodium (DSS)‑induced colitis. Firstly, meta‑analysis was used to explore whether the levels of IL‑18 were different in patients with colon cancer or inflammatory bowel disease. The results demonstrated that IL‑18 (rs187238, ‑137G/C) increased the incidence rate of colon cancer in patients, while IL‑18 (rs187238, ‑137G/C) decreased the incidence rate of ulcerative colitis or Crohn's disease in patients. Therefore, IL‑18 (rs187238, ‑137G/C) may have a dual function in colitis. Next, the functional role of IL‑18 in colitis was further investigated, by use of a DSS‑induced colitis mouse model. Pre‑treatment of the mice with IL‑18 increased body weight, augmented colon length, reduced inflammatory infiltration, promoted mucin (Muc)‑2 expression, increased the function and quantity of goblet cells and increased the mRNA levels of resistin‑like molecule (RELM) β and trefoil factor family (TFF) 3 in mice with DSS‑induced colitis, through the IL‑22/STAT3 pathway. By contrast, treatment with IL‑18 at later stages of the disease reduced body weight, decreased colon length, enhanced inflammatory infiltration and reduced Muc‑2 expression, decreased the function and quantity of goblet cells and inhibited the mRNA levels of RELMβ and TFF3 in mice with DSS‑induced colitis. In conclusion, IL‑18 served a dual function in colitis by regulating the function of goblet cells. The anti‑inflammatory effects of IL‑18 were observed in the early stage of colitis‑induced inflammation, while the pro‑inflammatory effects were observed in the later stages of the disease.
本研究的主要目的是探讨白细胞介素（IL）-18 在葡聚糖硫酸钠（DSS）诱导的结肠炎中的双重作用和机制。首先，采用荟萃分析探讨了结肠癌或炎症性肠病患者 IL-18 水平是否存在差异。结果表明，IL-18（rs187238，-137G/C）增加了结肠癌患者的发病风险，而 IL-18（rs187238，-137G/C）降低了溃疡性结肠炎或克罗恩病患者的发病风险。因此，IL-18（rs187238，-137G/C）在结肠炎中可能具有双重作用。接下来，通过 DSS 诱导的结肠炎小鼠模型进一步研究了 IL-18 在结肠炎中的功能作用。用 IL-18 预处理小鼠可增加体重、增加结肠长度、减少炎症浸润、促进粘蛋白（Muc）-2 表达、增加杯状细胞的功能和数量，并增加 DSS 诱导的结肠炎小鼠中抵抗素样分子（RELM）β和三叶因子家族（TFF）3 的 mRNA 水平，通过 IL-22/STAT3 通路。相比之下，在疾病的后期阶段用 IL-18 治疗会降低体重、减少结肠长度、增强炎症浸润并减少 Muc-2 表达、减少杯状细胞的功能和数量，并抑制 DSS 诱导的结肠炎小鼠中 RELMβ和 TFF3 的 mRNA 水平。综上所述，IL-18 通过调节杯状细胞的功能在结肠炎中发挥双重作用。在结肠炎诱导的炎症早期观察到 IL-18 的抗炎作用，而在疾病的后期阶段观察到促炎作用。
