Insulin-Like Growth Factor-1 Contributes to Mucosal Repair by β-Arrestin2-Mediated Extracellular Signal-Related Kinase Signaling in Experimental Colitis
Insulin-Like Growth Factor-1 Contributes to Mucosal Repair by β-Arrestin2-Mediated Extracellular Signal-Related Kinase Signaling in Experimental Colitis
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DOI：
10.1016/j.ajpath.2015.05.020
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发表时间：
2015-09-01
影响因子：
6
通讯作者：
Wu, Bin
中科院分区：
文献类型：
--
作者：
Chen, Tingting;Zheng, Fengping;Wu, Bin
胰岛素样生长因子-1（IGF-1）具有减轻肠道损伤和促进结肠炎粘膜修复的能力。β-Arrestins作为G蛋白偶联受体或非G蛋白偶联受体信号转导的支架蛋白，参与IGF-1介导的信号转导通路。然而，IGF-1和β-arrestin 2在实验性结肠炎的粘膜修复中的相互作用仍然未被探索。在β-arrestin 2野生型小鼠和β-arrestin 2敲除的同窝小鼠中通过使用3%葡聚糖硫酸钠5天诱导溃疡性结肠炎，然后定期饮水1、2、3和4周，以分析实验性结肠炎的粘膜修复。进行疾病活动指数和组织学评分分析。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和Ki-67染色法检测细胞凋亡和增殖。检测β-arrestin 2、磷酸化（p）-IGF-1 R和p-细胞外信号调节激酶（ERK）1/2的表达。此外，β-arrestin 2在HCT 116细胞中通过在体外IGF-1处理之前转染而过表达或改变。IGF-1和β-arrestin 2在实验性结肠炎修复期表达上调。靶向缺失β-arrestin 2通过抑制细胞增殖延迟结肠炎的修复，而不影响IGF-1和p-IGF-1 R的水平。β-arrestin 2/ERK信号通路通过促进实验性结肠炎上皮细胞和杯状细胞再生参与IGF-1介导的粘膜修复。这些结果表明，IGF-1有助于通过β-arrestin 2介导的ERK信号在实验性结肠炎的粘膜修复。
Insulin-Like growth factor-1 (IGF-1) possesses the ability to attenuate intestinal damage and promote mucosal repair of colitis. beta-Arrestins, as the scaffolding proteins of G protein-coupled receptors or non-G protein-coupled receptors signaling, can be involved in IGF-1 mediated signaling pathways. However, the interaction of IGF-1 and beta-arrestin2 in the mucosal repair of experimental colitis remains unexplored. Ulcerative colitis was induced in beta-arrestin2 wild-type mice and beta-arrestin2 knockout littermates by using 3% dextran sulfate sodium for 5 days, followed by regular water consumption for 1, 2, 3, and 4 weeks to analyze the mucosal repair from experimental colitis. Disease activity index and histologic score analyses were performed. Apoptosis and proliferation were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end Labeling and Ki-67 staining, respectively. The expressions of beta-arrestin2, phospho (p)-IGF-1R, and p-extracellular signal-regulated kinase (ERK)1/2 were examined. Furthermore, beta-arrestin2 was overexpressed or altered in HCT116 cells by transfection before IGF-1 treatment in vitro. IGF-1 and beta-arrestin2 expression was up-regulated in the repairing phase of experimental colitis. Targeted deletion of beta-arrestin2 delayed the repair of colitis by inhibiting cell proliferation without affecting the Levels of IGF-1 and p-IGF-1R. The beta-arrestin2/ERK signaling pathway was involved in IGF-1 mediated mucosal repair through promoting epithelial cell and goblet cell regeneration from experimental colitis. These results indicate that IGF-1 contributes to the mucosal repair by beta-arrestin2 mediated ERK signaling in experimental colitis.