Weaver D J, Poligone B, Bui T, Abdel-Motal U M, Baldwin A S, Tisch R
Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
J Immunol. 2001 Aug 1;167(3):1461-8. doi: 10.4049/jimmunol.167.3.1461.
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-kappaB, a transcription factor known to regulate IL-12 gene expression. Specifically, NOD DCs exhibit persistent hyperactivation of both IkappaB kinase and NF-kappaB in response to stimuli, in addition to selective degradation of IkappaBepsilon. Transfection of NOD DCs with a modified form of IkappaBalpha 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.
胰岛素依赖型糖尿病（IDDM）的特征是T细胞介导的胰岛素分泌β细胞破坏。因此，诸如巨噬细胞等抗原呈递细胞（APC）在该疾病过程中也被证明很重要。然而，具有强大APC功能的树突状细胞（DC）在IDDM中的作用仍不明确。在此，我们证明，源自非肥胖糖尿病（NOD）小鼠（一种IDDM模型）的DC与源自C57BL/6和BALB/c小鼠的DC相比，对各种形式的刺激更敏感，导致白细胞介素-12（IL-12）分泌增加。这种特性是核因子κB（NF-κB）过度激活的结果，NF-κB是一种已知可调节IL-12基因表达的转录因子。具体而言，NOD DC除了对IκBε进行选择性降解外，在受到刺激时还表现出IκB激酶和NF-κB的持续过度激活。用修饰形式的IκBα转染NOD DC可显著降低IL-12分泌，这表明NF-κB的过度激活部分导致了IL-12产生增加。预计NOD DC分泌IL-12的能力增强将有助于在致糖尿病反应过程中致病性辅助性T细胞1型（Th1，细胞毒性T细胞1型（Tc1））的发育。
