Identification of novel cytokine-induced genes in pancreatic β-cells by high-density oligonucleotide arrays
Identification of novel cytokine-induced genes in pancreatic β-cells by high-density oligonucleotide arrays
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DOI：
10.2337/diabetes.50.5.909
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发表时间：
2001-05-01
期刊：
影响因子：
7.7
通讯作者：
Eizirik, DL
中科院分区：
文献类型：
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作者：
Cardozo, AK;Kruhoffer, M;Eizirik, DL
1型糖尿病是一种自身免疫性疾病，由产生胰岛素的β细胞的选择性破坏引起。细胞因子可能导致1型糖尿病胰腺β细胞死亡。β-细胞暴露于白细胞介素（IL）-1 β诱导功能损伤，而β-细胞在IL-1 β和干扰素（INF）-γ存在下培养6-9天导致细胞凋亡。为了阐明细胞因子的这些作用所涉及的机制，我们研究了β细胞中苦参碱诱导的基因表达的一般模式。将原代大鼠β-细胞进行荧光激活细胞分选纯化，并暴露于对照条件、IL-1 β + INF-γ或单独的IL-1 β（仅24小时）6或24小时。通过寡核苷酸阵列一式两份地分析基因表达谱。在对照组和经苦参碱处理的β细胞中检测到近3，000个转录物。其中，96个和147个分别在暴露于IL-1 β + INF-γ 6小时和24小时后显示表达变化，而105个转录本在暴露于IL-1 β 24小时后被修饰。根据它们的生物学功能，将对精氨酸敏感的基因进行聚类。观察到的主要簇是代谢、信号转导、转录因子、蛋白质合成/加工、激素和相关受体。这些基因表达的改变可以解释β细胞中的一些细胞因子效应，如蛋白质生物合成和胰岛素释放减少。此外，存在多种细胞因子和趋化因子的诱导;这表明β细胞可能有助于胰岛炎期间单核细胞归巢。几个尼古丁诱导的基因可能受到转录因子NF-κ B的调控。澄清的功能，已确定的甜菜碱诱导的基因模式可能会揭开一些机制参与β细胞损伤和修复1型糖尿病。
Type 1 diabetes is an autoimmune disease resulting from the selective destruction of insulin-producing beta -cells. Cytokines may contribute to pancreatic beta -cell death in type 1 diabetes. beta -cell exposure to interleukin (IL)-1 beta induces functional impairment, whereas beta -cell culture for 6-9 days in the presence of IL-1 beta and interferon (INF)-gamma leads to apoptosis. To clarify the mechanisms involved in these effects of cytokines, we studied the general pattern of cytokine-induced gene expression in beta -cells. Primary rat beta -cells were fluorescence-activated cell sorter-purified and exposed for 6 or 24 h to control condition, IL-1 beta + INF-gamma, or IL-1 beta alone (24 h only). Gene expression profile was analyzed in duplicate by oligonucleotide arrays. Nearly 3,000 transcripts were detected in controls and cytokine-treated beta -cells. Of these, 96 and 147 displayed changes in expression after 6 and 24 h, respectively, of exposure to IL-1 beta + INF-gamma, whereas 105 transcripts were modified after a 24-h exposure to IL-1 beta. The cytokine-responsive genes were clustered according to their biological functions. The major clusters observed were metabolism, signal transduction, transcription factors, protein synthesis/processing, hormones, and related receptors. These modifications in gene expression may explain some of the cytokine effects in beta -cells, such as decreased protein biosynthesis and insulin release. In addition, there was induction of diverse cytokines and chemokines; this suggests that beta -cells may contribute to mononuclear cell homing during insulitis. Several of the cytokine-induced genes are potentially regulated by the transcription factor NF-kappaB. Clarification of the function of the identified cytokine-induced gene patterns may unveil some of the mechanisms involved in beta -cell damage and repair in type 1 diabetes.