The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis.
The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis.
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DOI：
10.1371/journal.pone.0025637
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Fiorucci S
中科院分区：
文献类型：
--
作者：
Cipriani S;Mencarelli A;Chini MG;Distrutti E;Renga B;Bifulco G;Baldelli F;Donini A;Fiorucci S
GP-BAR 1是G蛋白偶联受体超家族成员，是一种在回肠和结肠中高度表达的细胞表面胆汁酸激活受体。在单核细胞中，二级胆汁酸连接GP-BAR 1导致cAMP依赖性细胞因子生成减弱。研究GP-BAR 1在调节啮齿动物结肠炎模型肠道稳态和炎症驱动的免疫功能障碍中的作用。通过给予DSS和TNBS，在野生型和GP-BAR 1-/-小鼠中诱导了结肠炎。通过计算机筛选和计算对接研究鉴定潜在的GP-BAR 1激动剂。GP-BAR 1 −/−小鼠出现结肠粘液细胞形态异常和上皮紧密连接分子结构改变，伴连蛋白1表达增加和亚细胞分布异常，导致肠道通透性增加，并在生命早期对DSS作出反应，易患严重结肠炎。通过计算机筛选和对接研究，我们确定环丙沙星为GP-BAR 1配体。在单核细胞中，环丙沙星以GP-BAR 1依赖性方式增加cAMP浓度并减弱TLR 4连接诱导的TNFα释放。用环丙沙星和油酸（一种充分表征的GP-BAR 1配体）治疗TNBS引起的结肠炎小鼠，消除了结肠炎的体征和症状。结肠炎啮齿动物模型和克罗恩病患者组织中GP-BAR 1 mRNA的结肠表达增加流式细胞术分析表明，从TNBS处理的小鼠的固有层分离的约90%的CD 14+细胞对GP-BAR 1呈阳性染色。GP-BAR 1调节肠道屏障结构。其表达在结肠炎和克罗恩病的啮齿动物模型中增加。环丙沙星是GP-BAR 1配体。
GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation. To investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis. Colitis was induced in wild type and GP-BAR1−/− mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies. GP-BAR1−/− mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1. GP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand.