Dendritic cells from nonobese diabetic mice exhibit a defect in NF-κB regulation due to a hyperactive IκB kinase
Dendritic cells from nonobese diabetic mice exhibit a defect in NF-κB regulation due to a hyperactive IκB kinase
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DOI：
10.4049/jimmunol.167.3.1461
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发表时间：
2001-08-01
影响因子：
4.4
通讯作者：
Tisch, R
中科院分区：
文献类型：
--
作者：
Weaver, DJ;Poligone, B;Tisch, R
胰岛素依赖型糖尿病（IDDM）的特征是T细胞介导的对产生胰岛素的β细胞的破坏。因此，APC，如巨噬细胞，也已被证明在疾病过程中是重要的。然而，树突状细胞（DC），表现出强大的APC功能的作用（S）在IDDM中仍然不明确。在这里，我们证明，来自非肥胖糖尿病（NOD）小鼠，胰岛素依赖型糖尿病模型，DC更敏感的各种形式的刺激相比，从C57 BL/6和BALB/c小鼠，导致IL-12分泌增加。这种性质是NF-κ B超活化的结果，NF-κ B是一种已知调节IL-12基因表达的转录因子。具体地说，NOD DC除了选择性降解I kappaB激酶外，还表现出对刺激的持续性I kappaB激酶和NF kappaB超活化。用修饰形式的I kappaB α转染NOD DC显著降低IL-12分泌，表明NF-κ B的过度活化是IL-12产生增加的部分原因。NOD DCs分泌IL-12的能力增强，预计将有助于致病性Th 1（Tc 1）细胞在糖尿病反应过程中的发展。
Insulin-dependent diabetes mellitus (IDDM) is characterized by the T cell-mediated destruction of insulin-producing beta cells. Accordingly, APCs, such as macrophage, have also been shown to be important in the disease process. However, the role(s) of dendritic cells (DCs) that exhibit potent APC function remains undefined in IDDM. Here we demonstrate that DCs derived from nonobese diabetic (NOD) mice, a model for IDDM, are more sensitive to various forms of stimulation compared with those from C57BL/6 and BALB/c mice, resulting in increased IL-12 secretion. This property is a consequence of hyperactivation of NF-KB, a transcription factor known to regulate IL-12 gene expression. Specifically, NOD DCs exhibit persistent hyperactivation of both I kappaB kinase and NF kappaB in response to stimuli, in addition to selective degradation of I kappaB epsilon. Transfection of NOD DCs with a modified form of I kappaB alpha significantly reduced IL-12 secretion, suggesting that hyperactivation of NF-kappaB was in part responsible for increased IL-12 production. An enhanced capacity of NOD DCs to secrete IL-12 would be expected to contribute to the development of pathogenic Th1 (Tc1) cells during the diabetogenic response.