Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer
Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer
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DOI：
10.1111/jgh.12435
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发表时间：
2014-03-01
影响因子：
4.1
通讯作者：
Kim, Joo Sung
中科院分区：
文献类型：
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作者：
Koh, Seong-Joon;Kim, Jung Mogg;Kim, Joo Sung
背景与目的探讨二甲双胍对肠道炎症的影响。荧光素酶法和实时荧光定量PCR法检测IL-8的表达。通过蛋白质印迹法评价kappaB（IB）磷酸化/降解抑制剂和腺苷单磷酸活化蛋白激酶（AMPK）活性。用电泳迁移率变动分析法测定转录因子核因子-κ B（NF-B）的DNA结合活性。在急性结肠炎模型中，给予小鼠4%葡聚糖硫酸钠（DSS）5天。使用IL-10（-/-）小鼠评价二甲双胍对慢性结肠炎的影响。在炎症相关的肿瘤模型中，小鼠给予单次腹腔注射氧化偶氮甲烷，然后由3个周期的2%DSS为5天和2周的自由waterconsumption. ResultsMetastatin显着抑制IL-8诱导科洛205细胞刺激TNF-α。二甲双胍减弱IB磷酸化和NF-B DNA结合活性。二甲双胍给药显著降低了DSS诱导的结肠炎的严重程度。此外，DSS诱导的IB激酶（IKK）活化在二甲双胍处理的小鼠中显著降低。二甲双胍显著减弱IL-10（-/-）小鼠结肠炎的严重程度，诱导肠上皮细胞中AMPK活性，并抑制小鼠结肠癌的发展。结论这些结果表明二甲双胍抑制肠上皮细胞中NF-B活化，并改善小鼠结肠炎和结肠炎相关的小鼠肿瘤发生。提示二甲双胍可能是治疗炎症性肠病的潜在治疗剂。
Background and AimThe aim of this study is to evaluate the effect of metformin on intestinal inflammation.MethodsCOLO205 cells were pretreated with metformin and stimulated with tumor necrosis factor (TNF)-. Expression of interleukin (IL)-8 was determined by luciferase assay and real-time PCR. Inhibitor of kappaB (IB) phosphorylation/degradation and adenosine monohosphate-activated protein kinase (AMPK) activity were evaluated by Western blotting. DNA-binding activity of transcription factor nuclear factor-kappaB (NF-B) was assessed by electrophoretic mobility shift assay. In an acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days. IL-10(-/-) mice were used to evaluate the effect of metformin on chronic colitis. In an inflamation-associated tumor model, mice were given a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption.ResultsMetformin significantly inhibited IL-8 induction in COLO 205 cells stimulated with TNF-. Metformin attenuated IB phosphorylation and NF-B DNA-binding activity. Administration of metformin significantly reduced the severity of DSS-induced colitis. In addition, DSS-induced IB kinase (IKK) activation was significantly reduced in mice treated with metformin. Metformin significantly attenuated the severity of colitis in IL-10(-/-) mice, induced AMPK activity in intestinal epithelial cells, and inhibited the development of colitic cancer in mice.ConclusionsThese results indicate that metformin suppresses NF-B activation in intestinal epithelial cells and ameliorates murine colitis and colitis-associated tumorigenesis in mice, suggesting that metformin could be a potential therapeutic agent for the treatment of inflammatory bowel disease.