Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, USA.
Diabetologia. 2013 Jan;56(1):126-35. doi: 10.1007/s00125-012-2732-9. Epub 2012 Oct 3.
AIMS/HYPOTHESIS: IL-12 is an important cytokine in early inflammatory responses and is implicated in the immune-mediated pathogenesis of pancreatic islets in diabetes. However, little is known about the direct effects of IL-12 on islets and beta cells.
In this study, beta cell function, gene expression and protein production were assessed in primary human donor islets and murine beta cell lines in response to stimulation with IL-12 or a pro-inflammatory cytokine cocktail (TNF-α, IL-1β and IFN-γ).
The pro-inflammatory cytokine cocktail induced islet dysfunction and potently increased the expression and production of IL-12 ligand and IL-12 receptor in human islets. In human islets, the receptor for IL-12 co-localised to the cell surface of insulin-producing cells. Both IL-12 ligand and IL-12 receptor are expressed in the homogeneous beta cell line INS-1. IL-12 induced changes in gene expression, including a dose-dependent upregulation of IFNγ (also known as IFNG), in INS-1 cells. A neutralising antibody to IL-12 directly inhibited IFNγ gene expression in human donor islets induced by either IL-12 or pro-inflammatory cytokine stimulation. Functionally, IL-12 impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells and human donor islets. A neutralising antibody to IL-12 reversed the beta cell dysfunction (uncoupling of GSIS or induction of caspase-3 activity) induced by pro-inflammatory cytokines.
CONCLUSIONS/INTERPRETATION: These data identify beta cells as a local source of IL-12 ligand and suggest a direct role of IL-12 in mediating beta cell pathology.
目的/假设：IL-12 是早期炎症反应中的重要细胞因子，与糖尿病中胰岛的免疫介导发病机制有关。然而，关于 IL-12 对胰岛和β细胞的直接作用知之甚少。
在这项研究中，我们评估了原代人供体胰岛和鼠β细胞系在受到 IL-12 或促炎细胞因子鸡尾酒（TNF-α、IL-1β和 IFN-γ）刺激时的β细胞功能、基因表达和蛋白产生情况。
促炎细胞因子鸡尾酒诱导胰岛功能障碍，并强烈增加人胰岛中 IL-12 配体和 IL-12 受体的表达和产生。在人胰岛中，IL-12 的受体与胰岛素分泌细胞的细胞表面共定位。IL-12 配体和 IL-12 受体均在均质的β细胞系 INS-1 中表达。IL-12 诱导基因表达的变化，包括 INS-1 细胞中 IFNγ（也称为 IFNG）的剂量依赖性上调。抗 IL-12 的中和抗体直接抑制了由 IL-12 或促炎细胞因子刺激诱导的人供体胰岛中 IFNγ 基因的表达。在功能上，IL-12 损害了 INS-1 细胞和人供体胰岛的葡萄糖刺激的胰岛素分泌（GSIS）。抗 IL-12 的中和抗体逆转了促炎细胞因子诱导的β细胞功能障碍（GSIS 脱偶联或 caspase-3 活性诱导）。
结论/解释：这些数据将β细胞鉴定为 IL-12 配体的局部来源，并表明 IL-12 在介导β细胞病理学方面具有直接作用。
