Metformin Ameliorates Inflammatory Bowel Disease by Suppression of the STAT3 Signaling Pathway and Regulation of the between Th17/Treg Balance.
Metformin Ameliorates Inflammatory Bowel Disease by Suppression of the STAT3 Signaling Pathway and Regulation of the between Th17/Treg Balance.
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DOI：
10.1371/journal.pone.0135858
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Cho ML
中科院分区：
文献类型：
--
作者：
Lee SY;Lee SH;Yang EJ;Kim EK;Kim JK;Shin DY;Cho ML
2型糖尿病的治疗方法有哪些？在炎症性肠病（IBD）小鼠模型中，我们试图确定二甲双胍是否通过调节p-信号转导子和转录激活子3（STAT 3）表达和辅助性T细胞17（Th 17）增殖来减轻炎症。IBD小鼠给予二甲双胍16天，并分析其组织。采用免疫组化和共聚焦显微镜检测脾脏和淋巴结中AMP活化蛋白激酶（AMPK）、雷帕霉素靶蛋白（mTOR）、p-STAT 3和p-STAT 5的表达。使用定量PCR测定基因表达，并使用蛋白质印迹和酶联免疫吸附试验测定蛋白质表达水平。采用MTT法检测HT-29细胞增殖情况。二甲双胍降低疾病活动指数评分并抑制体重减轻。二甲双胍还降低了结肠组织学评分和炎症介质，并增加了结肠长度。二甲双胍治疗可抑制白细胞介素（IL）-17、p-STAT 3和p-mTOR的表达。相比之下，二甲双胍处理增加了p-AMPK和Foxp 3的表达水平。此外，在与不同浓度的二甲双胍一起培养的发炎的人HT-29细胞中，炎性细胞因子的表达以剂量依赖性方式降低。二甲双胍通过抑制p-STAT 3和IL-17表达减轻IBD严重程度并减少炎症。我们的研究结果增加了我们对这种慢性炎症性疾病的理解，并支持使用p-STAT 3抑制剂治疗IBD的策略。
Metformin is used to treat type 2 diabetes. We sought to determine whether metformin reduces inflammation, by regulating p-signal transducer and activator of transcription 3 (STAT3) expression and T-helper 17 (Th17) cell proliferation, in a mouse model of inflammatory bowel disease (IBD). IBD mice were administered metformin for 16 days and their tissues were analyzed. AMP-activated protein kinase (AMPK), the mammalian target of rapamycin (mTOR), p-STAT3 and p-STAT5 in the spleen and lymph nodes were detected using immunohistochemistry and confocal microscopy. Gene expression was determined using quantitative PCR assays, and protein expression levels were measured using western blotting and enzyme-linked immunosorbent assays. Human HT-29 cell proliferation was evaluated using MTT assays. Metformin reduced disease activity index scores and inhibited weight loss. Metformin also decreased the colonic histological score and inflammatory mediators and increased colon lengths increased. Treatment with metformin inhibited the expression of interleukin (IL)-17, p-STAT3, and p-mTOR. In contrast, metformin treatment increased expression levels of p-AMPK and Foxp3. In addition, expression of inflammatory cytokines decreased in a dose-dependent manner in inflamed human HT-29 cells cultured with metformin at various concentrations. Metformin attenuates IBD severity and reduces inflammation through the inhibition of p-STAT3 and IL-17 expression. Our results have increased our understanding of this chronic inflammatory disease, and support the strategy of using p-STAT3 inhibitors to treat IBD.