Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA.
Islets. 2009 Jul-Aug;1(1):34-41. doi: 10.4161/isl.1.1.8629.
Osteopontin (OPN) is a secreted acidic phosphoprotein that is involved in many inflammatory and immune-modulating disorders. We previously demonstrated that OPN is a novel islet protein and a pro survival factor that may serve as an intrinsic feedback regulator of nitric oxide signaling in β-cells. Here, we investigated the endogenous expression of pancreatic OPN in non obese diabetic (NOD) mice and explored its regulation in the islets and b-cells. High levels of pancreatic OPN mRNA and protein were seen in the prediabetic NOD mice pancreata. The temporal pattern of OPN expression inversely correlated with progression of insulitis and β-cell destruction. Immunostaining of pancreatic serial sections showed co localization of OPN with most of the islet hormones. Next we investigated the regulation of OPN in the islets and β-cells. Naturally occurring early upregulation of OPN transcription was seen after exposure of native normoglycemic NOD islets and β-cells to a high-dose combination of IL-1β, TNF-α and IFN-γ. To distinguish between the effect of cytokines and high glucose on OPN transcription, RINm5F cells were transfected with luciferase-labeled rat OPN promoter and treated with cytokines or glucose. Cytokines induced upregulation of OPN promoter activity within one hour, while glucose induced a dose-dependent upregulation of OPN promoter activity after 24 hrs. Long-term exposures to cytokines or glucose reduced OPN expression and promoter activity. Our data provide the first observations into the presence of a positive intrinsic mechanism that regulates pancreatic OPN expression. Based upon previous studies that support a protective role of OPN in the islets, our data suggest that exhaustion of this local OPN system is implicated in the associated loss of endogenous islet protection and progression of the destructive insulitis and diabetes severity in the NOD mouse model.
骨桥蛋白 (OPN) 是一种分泌性酸性磷蛋白，参与多种炎症和免疫调节紊乱。我们之前的研究表明，OPN 是一种新型胰岛蛋白和生存促进因子，可能作为β细胞中一氧化氮信号的内在反馈调节剂。在这里，我们研究了非肥胖型糖尿病 (NOD) 小鼠胰腺中内源性 OPN 的表达，并探讨了其在胰岛和β细胞中的调节作用。在糖尿病前期的 NOD 小鼠胰腺中，观察到胰腺 OPN 的 mRNA 和蛋白水平较高。OPN 表达的时间模式与胰岛炎和β细胞破坏的进展呈负相关。胰腺连续切片的免疫染色显示 OPN 与大多数胰岛激素的共定位。接下来，我们研究了 OPN 在胰岛和β细胞中的调节作用。在将天然正常血糖的 NOD 胰岛和β细胞暴露于高剂量的 IL-1β、TNF-α 和 IFN-γ 后，观察到 OPN 转录的自然早期上调。为了区分细胞因子和高血糖对 OPN 转录的影响，用荧光素酶标记的大鼠 OPN 启动子转染 RINm5F 细胞，并对其进行细胞因子或葡萄糖处理。细胞因子在一小时内诱导 OPN 启动子活性的上调，而葡萄糖在 24 小时后诱导 OPN 启动子活性的剂量依赖性上调。长期暴露于细胞因子或葡萄糖会降低 OPN 的表达和启动子活性。我们的数据提供了关于调节胰腺 OPN 表达的正内在机制存在的第一个观察结果。基于先前支持 OPN 在胰岛中具有保护作用的研究，我们的数据表明，这种局部 OPN 系统的耗竭与相关的内源性胰岛保护丧失以及 NOD 小鼠模型中破坏性胰岛炎和糖尿病严重程度的进展有关。
