Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice
Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice
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DOI：
10.1124/mol.63.6.1289
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发表时间：
2003-06-01
影响因子：
3.6
通讯作者：
Knepel, W
中科院分区：
文献类型：
--
作者：
Oetjen, E;Baun, D;Knepel, W
环孢素A和他克莫司是临床上重要的免疫抑制药物。它们共同的致糖尿病作用是它们最严重的不良反应之一。其潜在机制尚不清楚。以往的研究表明，他克莫司在高浓度下可抑制肿瘤细胞系中胰岛素基因的转录。为了研究正常成熟胰岛细胞中胰岛素基因的转录，我们采用了一种新的方法。产生携带人胰岛素启动子-报告基因的转基因小鼠。人胰岛素启动子在胰岛中指导转录，并在分离的胰岛中对报告基因表达赋予正常的生理葡萄糖应答。葡萄糖刺激后，他克莫司和环孢素A在很大程度上（约70%）抑制正常成熟胰岛细胞中人胰岛素启动子介导的基因表达，并且在已知抑制钙调磷酸酶活性的浓度下具有高效力（IC 50值分别为1和35 nM）。此外，葡萄糖刺激小鼠胰岛中的钙调神经磷酸酶活性，进一步支持钙调神经磷酸酶活性是葡萄糖信号传导至人胰岛素基因的重要部分的观点。环孢菌素A和他克莫司在正常胰岛中的高效力表明，环孢菌素A和他克莫司对胰岛素基因转录的抑制在临床上是重要的，并且是这些免疫抑制药物的致糖尿病作用的机制之一。
Cyclosporin A and tacrolimus are clinically important immunosuppressive drugs. They share a diabetogenic action as one of their most serious adverse effects. The underlying mechanism is unknown. Previous studies have shown that tacrolimus can inhibit insulin gene transcription at high concentrations in tumor cell lines. To study insulin gene transcription in normal, mature pancreatic islet cells, we used a novel approach in the present study. Transgenic mice that carry a human insulin promoter-reporter gene were generated. The human insulin promoter directed transcription in pancreatic islets and conferred a normal, physiological glucose response to reporter gene expression in isolated islets. After stimulation with glucose, human insulin promoter-mediated gene expression was inhibited in normal, mature islet cells by both tacrolimus and cyclosporin A to a large extent ( approximately 70%) and with high potency at concentrations that are known to inhibit calcineurin phosphatase activity (IC50 values of 1 and 35 nM, respectively). Furthermore, glucose stimulated calcineurin phosphatase activity in mouse pancreatic islets, further supporting the view that calcineurin phosphatase activity is an essential part of glucose signaling to the human insulin gene. The high potency of cyclosporin A and tacrolimus in normal islets suggests that inhibition of insulin gene transcription by cyclosporin A and tacrolimus is clinically important and is one mechanism of the diabetogenic effect of these immunosuppressive drugs.