PDF(Pubmed)
Abstract：
Cytokine-induced β-cell apoptosis is a major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding its underlying mechanisms, few drugs have been translated to protect β-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (bromo- and extra-terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in an NOD (non-obese diabetes) mouse model of T1D. However, the effect of BET protein inhibition on β-cell function in response to cytokines is unknown. Here, we demonstrate that I-BET, a BET protein inhibitor, protected β-cells from cytokine-induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced β-cell apoptosis, suggesting a cytoprotective function. Mechanistically, I-BET treatment inhibited cytokine-induced NF-kB signaling and enhanced FOXO1-mediated anti-oxidant response in β-cells. RNA-Seq analysis revealed that I-BET treatment also suppressed pathways involved in apoptosis while maintaining the expression of genes critical for β-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting β-cells from cytokine-induced dysfunction and apoptosis, and targeting BET proteins could have potential therapeutic value in preserving β-cell functional mass in T1D.
摘要：
细胞因子诱导的β细胞凋亡是1型糖尿病（T1D）的主要致病机制。尽管在理解其潜在机制方面取得了重大进展，很少有药物被翻译来保护T1D中的β细胞。表观遗传调节剂如含溴结构域的BET(溴-和外-末端)蛋白是免疫应答的重要调节剂。临床前研究已经证明BET抑制剂在T1D的NOD(非肥胖糖尿病)小鼠模型中的保护作用。然而,BET蛋白抑制对响应细胞因子的β细胞功能的影响尚不清楚。这里,我们证明了I-BET，一种BET蛋白抑制剂,保护β细胞免受细胞因子诱导的功能障碍和死亡。对暴露于低剂量STZ（链脲佐菌素）的小鼠体内施用I-BET，T1D的模型，显著减少β细胞凋亡，提示细胞保护功能。机械上,I-BET治疗抑制细胞因子诱导的NF-kB信号传导并增强FOXO1介导的β细胞抗氧化反应。RNA-Seq分析显示，I-BET处理还抑制参与细胞凋亡的途径，同时维持β细胞功能关键基因的表达，例如Pdx1和Ins1。一起来看,这项研究表明，I-BET可有效保护β细胞免受细胞因子诱导的功能障碍和凋亡，和靶向BET蛋白可能在保留T1D中的β细胞功能质量方面具有潜在的治疗价值。
