TPL2抑制剂对溃疡性结肠炎小鼠的作用及机制研究

Effect and mechanism of TPL2 inhibitor in mice with ulcerative colitis

目的探讨抑制肿瘤进展位点2(tumor progression locus 2,TPL2)/细胞外信号调节激酶1/2(extracellular signal-regulated kinase1/2,ERK1/2)信号通路对实验性溃疡性结肠炎(ulcerative colitis,UC)小鼠肠道损伤和炎症的保护作用。方法将30只C57BL/6J小鼠分为正常对照组、模型对照组、高剂量TPL2抑制剂组、低剂量TPL2抑制剂组、美沙拉嗪组,每组6只。比较各组小鼠疾病活动指数(disease activity index,DAI)和组织学损伤评估(histological index,HI)评分,采用实时定量PCR检测结肠中IL-6、TNF-α、TPL2和ERK1/2 mRNA表达水平,Western blotting检测结肠中TPL2、ERK1/2蛋白表达水平。结果与正常对照组相比较,模型对照组小鼠的DAI、HI评分均升高,结肠中IL-6、TNF-α、TPL2、ERK1/2 mRNA和蛋白表达均增加(均P<0.05)。与模型对照组相比较,给予TPL2抑制剂干预的两组小鼠DAI、HI评分均降低,结肠中IL-6、TNF-αmRNA相对表达量降低,结肠中TPL2、ERK1/2 mRNA和蛋白表达均下降(均P<0.05)。结论TPL2抑制剂可以改善UC小鼠肠道组织损伤与炎症,其分子机制与抑制其下游ERK1/2信号通路相关。

Objective To investigate the protective effect of tumor progression locus 2(TPL2)/extracellular signal-regulated kinase1/2(ERK1/2)signaling pathway on intestinal tissue damage and inflammation in mice with experimental ulcerative colitis(UC).Methods Thirty C57BL/6J mice were divided into normal control group,model control group,high-dose TPL2 inhibitor group,low-dose TPL2 inhibitor group and Mesalazine group,with 6 mice in each group.Disease activity index(DAI)and histological index(HI)score of each group were compared,and the mRNA expression levels of IL-6,TNF-α,TPL2 and ERK1/2 in colon were detected by Real-time PCR.The protein expression levels of TPL2 and ERK1/2 in colon were detected by Western blotting.Results Compared with normal control group,DAI and HI scores of model control group were increased、IL-6 and TNF-α,TPL2 and ERK1/2 mRNA relative expression levels in colon were increased、mRNA and protein expression levels in colon were increased(all P<0.05).Compared with model control group,DAI and HI scores of mice in both groups treated with TPL2 inhibitor were decreased.The relative expression levels of IL-6 and TNF-αmRNA in colon were decreased,and the expression levels of TPL2 and ERK1/2 mRNA and protein in colon were decreased(all P<0.05).Conclusion TPL2 inhibitor can improve intestinal tissue damage and inflammation in UC mice,and its molecular mechanism is associated with the inhibition of the downstream ERK1/2 signaling pathway.