Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic beta-cells.
Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic beta-cells.
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作者：
Roggli E;Britan A;Gattesco S;Lin-Marq N;Abderrahmani A;Meda P;Regazzi R
暴露于促炎细胞因子的胰腺β细胞显示基因表达的改变，导致胰岛素分泌缺陷和细胞凋亡。microRNA是一种小的非编码RNA，是基因表达的关键调控因子。在这里，我们评估了microRNA对马槟榔碱介导的β细胞毒性的贡献。我们使用全局微阵列分析和实时PCR分析来检测暴露于细胞因子的β细胞和糖尿病前期NOD小鼠胰岛中microRNA表达的变化。我们通过改变分泌胰岛素的MIN 6细胞中的表达来评估受细胞因子介导的β细胞衰竭影响的微小RNA的参与程度。我们发现IL-1β和TNF-α诱导MIN 6细胞和人胰岛中miR-21、miR-34 a和miR-146 a的表达。我们进一步表明，在糖尿病前期胰岛炎的发展过程中，NOD小鼠的胰岛中这些microRNA增加。使用反义分子阻断miR-21、miR-34 a或miR-146 a功能不能恢复胰岛素启动子活性，但可防止IL-1β暴露后观察到的葡萄糖诱导的胰岛素分泌减少。此外，抗-miR-34 a和抗-miR-146 a处理保护MIN 6细胞免于甘氨酸触发的细胞死亡。我们的数据鉴定了miR-21、miR-34 a和miR-146 a作为促炎细胞因子在体外和体内引起的β细胞衰竭的新参与者，特别是在NOD小鼠中明显糖尿病之前的胰岛周围炎的发展期间。
Pancreatic β-cells exposed to proinflammatory cytokines display alterations in gene expression resulting in defective insulin secretion and apoptosis. MicroRNAs are small noncoding RNAs emerging as key regulators of gene expression. Here, we evaluated the contribution of microRNAs to cytokine-mediated β-cell cytotoxicity. We used global microarray profiling and real-time PCR analysis to detect changes in microRNA expression in β-cells exposed to cytokines and in islets of pre-diabetic NOD mice. We assessed the involvement of the microRNAs affected in cytokine-mediated β-cell failure by modifying their expression in insulin-secreting MIN6 cells. We found that IL-1β and TNF-α induce the expression of miR-21, miR-34a, and miR-146a both in MIN6 cells and human pancreatic islets. We further show an increase of these microRNAs in islets of NOD mice during development of pre-diabetic insulitis. Blocking miR-21, miR-34a, or miR-146a function using antisense molecules did not restore insulin-promoter activity but prevented the reduction in glucose-induced insulin secretion observed upon IL-1β exposure. Moreover, anti–miR-34a and anti–miR-146a treatment protected MIN6 cells from cytokine-triggered cell death. Our data identify miR-21, miR-34a, and miR-146a as novel players in β-cell failure elicited in vitro and in vivo by proinflammatory cytokines, notably during the development of peri-insulitis that precedes overt diabetes in NOD mice.
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