STAT1 Is a Master Regulator of Pancreatic β-Cell Apoptosis and Islet Inflammation
STAT1 Is a Master Regulator of Pancreatic β-Cell Apoptosis and Islet Inflammation
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DOI：
10.1074/jbc.m110.162131
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发表时间：
2011-01-14
影响因子：
4.8
通讯作者：
Eizirik, Decio L.
中科院分区：
文献类型：
--
作者：
Moore, Fabrice;Naamane, Najib;Eizirik, Decio L.
胰岛浸润免疫细胞产生的细胞因子诱导1型糖尿病患者β细胞凋亡IFN-γ调节的转录因子STAT 1/IRF-1对β细胞具有明显不同的作用。因此，STAT 1促进细胞凋亡和炎症，而IRF-1下调炎症介质。为了理解这些差异结果在单一信号转导通路中的分子基础，我们目前表征了β细胞中由STAT 1和IRF-1调控的基因网络。这是通过使用SiRNA方法与暴露或未暴露于IL-1 β和IFN-γ的胰岛素产生细胞的微阵列分析相结合来完成的。在INS-1 E细胞和原代大鼠β细胞中进一步研究了相关的微阵列发现。STAT 1而不是IRF-1介导了精氨酸诱导的分化β细胞表型的丧失，如胰岛素、Pdx 1、MafA和Glut 2降低所示。此外，STAT 1通过上调促凋亡蛋白DP 5来调节精氨酸诱导的细胞凋亡。STAT 1和IRF-1对精氨酸诱导的趋化因子产生具有相反的作用，IRF-1对STAT 1和下游趋化因子表达产生负反馈抑制。本研究阐明了IFN-γ/STAT 1/IRF-1轴控制β细胞功能/分化、死亡和胰岛炎症的转录网络。
Cytokines produced by islet-infiltrating immune cells induce beta-cell apoptosis in type 1 diabetes. The IFN-gamma-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on beta-cells. Thus, STAT1 promotes apoptosis and inflammation, whereas IRF-1 down-regulates inflammatory mediators. To understand the molecular basis for these differential outcomes within a single signal transduction pathway, we presently characterized the gene networks regulated by STAT1 and IRF-1 in beta-cells. This was done by using siRNA approaches coupled to microarray analysis of insulin-producing cells exposed or not to IL-1 beta and IFN-gamma. Relevant microarray findings were further studied in INS-1E cells and primary rat beta-cells. STAT1, but not IRF-1, mediates the cytokine-induced loss of the differentiated beta-cell phenotype, as indicated by decreased insulin, Pdx1, MafA, and Glut2. Furthermore, STAT1 regulates cytokine-induced apoptosis via up-regulation of the proapoptotic protein DP5. STAT1 and IRF-1 have opposite effects on cytokine-induced chemokine production, with IRF-1 exerting negative feedback inhibition on STAT1 and downstream chemokine expression. The present study elucidates the transcriptional networks through which the IFN-gamma/STAT1/IRF-1 axis controls beta-cell function/differentiation, demise, and islet inflammation.