c-Jun氨基末端激酶选择性抑制剂对葡聚糖硫酸钠诱导的小鼠结肠炎的影响

Treatment with SP600125,a selective JNK inhibitor,down-regulates the levels of TNF-α in the intestinal mucosa and IL-6 in the serum of mice with DSS-induced ulcerative colitis

目的:探讨c-Jun氨基末端激酶(JNK)选择性抑制剂SP600125对葡聚糖硫酸钠(DSS)诱导的急性期溃疡性结肠炎小鼠结肠组织内肿瘤坏死因(TNF)α的表达情况及血清白介素(IL)-6含量的影响.方法:40只♂C57BL/6小鼠随机分成5组,每组8只.正常对照组(A组)、DSS模型组(B组)、SP600125低剂量组(C组)、SP600125高剂量组(D组)、DMSO载体组(E组).A组小鼠饮用蒸馏水7d;B-E组小鼠饮用3%DSS水溶液7d.C组和D组小鼠分别以低、高剂量SP600125腹腔内注射,E组只给SP600125的载体DMSO,给药方式同前.造模及干预7d后处死小鼠,观察指标包括:疾病活动指数(disease active index,DAI)、组织学损伤的评估(histological index,HI);免疫组织化学法检测各组结肠黏膜p-JNK和TNF-α的变化,ELISA检测血清IL-6的水平.结果:造模第8天,B与E组之间的各项检测指标的差异均无统计学意义(均P>0.05);B组的DAI、HI都明显高于A组(8.00±1.41vs0.25±0.16;5.88±0.99vs0.50±0.93,均P<0.01),C组的DAI与B组相比无显著性差异(P>0.05),D组的DAI明显低于B组(4.38±1.51vs8.00±1.41,P<0.01),C、D组的HI都明显低于B组(3.88±1.46vs5.88±0.99;2.63±0.74vs5.88±0.99,均P<0.01);B组结肠黏膜的p-JNK、TNF-α及血清IL-6都明显高于A组(99.01±10.75vs116.41±10.46;103.39±11.09vs120.24±10.67;183.34±25.87vs75.91±20.27,均P<0.01),各项在C、D组中的水平都明显低于B组(105.94±10.93vs99.01±10.75;110.21±11.05vs103.39±11.09;140.37±32.07vs183.34±25.87;114.52±11.06vs99.01±10.75;117.87±11.00vs103.39±11.09;108.61±20.34vs183.34±25.87,均P<0.01).结论:SP600125通过下调p-JNK表达,降低小鼠结肠黏膜促炎因子TNF-α表达及血清IL-6的含量而发挥其干预作用.

AIM：To evaluate the infl uence of SP600125,a selective c-Jun N-terminal kinase（JNK） inhibitor,on the levels of tumor necrosis factor-α（TNF-α） in the intestinal mucosa and interleukin-6（IL-6） in the serum of mice with dextran sulfate sodium（DSS）-induced ulcerative colitis（UC）.METHODS：Forty male C57BL/6 mice were randomly assigned to five groups：normal control group,model control group,low-dose SP600125 group,large-dose SP600125 group,and DMSO group.Except that the normal control group was given distilled water,animals of other groups were given 3% DSS in drinking water for 7 days to induce acute intestinal inflammation.Mice of the low-and large-dose SP600125 groups also received intraperitoneal injection of SP600125,while the DMSO group received DMSO.All animals were sacrificed on day 8 after treatment.The disease activity index（DAI） and histological index（HI） were calculated,the expression of p-JNK and TNF-α in the intestinal mucosa was measured by immunohistochemistry,and the level of IL-6 in the serum was measured by ELISA.RESULTS：On day 8 after DSS exposure,DAI and HI showed no signif icant difference between the model control group and DMSO group E（both P 0.05） but were significantly higher in the model control group than in the normal control group（8.00 ± 1.41 vs 0.25 ± 0.16;5.88 ± 0.99 vs 0.50 ± 0.93,both P 0.01）.Although there was no significant difference in DAI between the low-dose SP600125 group and model control group（P 0.05）,DAI was significantly lower in the large-dose SP600125 group than in the model control group（4.38 ± 1.51 vs 8.00 ± 1.41,P 0.01）.HI in the two SP600125 groups were significantly lower than those in the model control group（3.88 ± 1.46 vs 5.88 ± 0.99;2.63 ± 0.74 vs 5.88 ± 0.99,both P 0.01）.The levels of p-JNK and TNF-α in the intestinal mucosa and that of IL-6 in the serum were significantly higher in the model control than in normal control group（99.01 ± 10.75 vs 116.41 ± 10.46;103.39 ± 11.09 vs 120.24 ± 10.67;183.34 ± 25.87 vs 75.91 ± 20.27,all P0.01）,but were signif icantly lower in the two SP600125 groups than in the model control group（105.94 ± 10.93 vs 99.01 ± 10.75;110.21 ± 11.05 vs 103.39 ± 11.09;140.37 ± 32.07 vs 183.34 ± 25.87;114.52 ± 11.06 vs 99.01 ± 10.75;117.87 ± 11.00 vs 103.39 ± 11.09;108.61 ± 20.34 vs 183.34 ± 25.87,all P 0.01）.CONCLUSION：Treatment with SP600125 can down-regulate the expression of p-JNK and TNF-α in the intestinal mucosa and IL-6 in the serum of mice with experimental UC.