Production and function of IL-12 in islets and beta cells.
Production and function of IL-12 in islets and beta cells.
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DOI：
10.1007/s00125-012-2732-9
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发表时间：
2013-01
期刊：
影响因子：
8.2
通讯作者：
Nadler, J. L.
中科院分区：
文献类型：
--
作者：
Taylor-Fishwick, D. A.;Weaver, J. R.;Grzesik, W.;Chakrabarti, S.;Green-Mitchell, S.;Imai, Y.;Kuhn, N.;Nadler, J. L.
IL-12在早期炎症反应中是一个重要的细胞因子，并与糖尿病胰岛的免疫介导发病机制有关。然而，人们对IL-12对胰岛和β细胞的直接影响知之甚少。在这项研究中，研究人员评估了原代人供体胰岛和小鼠β细胞系对IL-12或促炎细胞因子混合物（TNF-α、IL-1β和IFN-γ）刺激的β细胞功能、基因表达和蛋白质产生。促炎细胞因子鸡尾酒可诱导胰岛功能障碍，并显著增加人胰岛IL-12配体和IL-12受体的表达和产生。在人类胰岛中，IL-12受体共定位于胰岛素生成细胞的细胞表面。IL-12配体和IL-12受体均在均相β细胞系INS-1中表达。IL-12诱导INS-1细胞中基因表达的变化，包括IFNγ（也称为IFNG）的剂量依赖性上调。IL-12中和抗体直接抑制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会损害INS-1细胞和人供体胰岛的葡萄糖刺激胰岛素分泌（GSIS）。IL-12的中和抗体可逆转由促炎细胞因子诱导的β细胞功能障碍（GSIS解偶联或诱导caspase-3活性）。这些数据确定β细胞是IL-12配体的局部来源，并提示IL-12在介导β细胞病理中的直接作用。
IL-12 is an important cytokine in early inflammatory responses and is implicated in the immunemediated 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. 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.
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影响因子：
7.4
作者：
Lenzen, S;Drinkgern, J;Tiedge, M
通讯作者：
Tiedge, M
影响因子：
7.7
作者：
Azevedo-Martins, AK;Lortz, S;Tiedge, M
通讯作者：
Tiedge, M
影响因子：
56.9
作者：
KATZ, JD;BENOIST, C;MATHIS, D
通讯作者：
MATHIS, D
影响因子：
7.7
作者：
Jörns, A;Günther, A;Lenzen, S
通讯作者：
Lenzen, S
影响因子：
2.9
作者：
Catalan, Victoria;Gomez-Ambrosi, Javier;Fruehbeck, Gema
通讯作者：
Fruehbeck, Gema