Regulation of insulin gene expression by cytokines and cell-cell interactions in mouse medullary thymic epithelial cells
Regulation of insulin gene expression by cytokines and cell-cell interactions in mouse medullary thymic epithelial cells
复制标题
DOI：
10.1007/s00125-009-1448-y
复制
发表时间：
2009-10-01
期刊：
影响因子：
8.2
通讯作者：
Polychronakos, C.
中科院分区：
文献类型：
--
作者：
Levi, D.;Polychronakos, C.
胸腺组织特异性自身抗原的表达对自身耐受至关重要。1型糖尿病的遗传易感性与胸腺胰岛素表达呈负相关，在小鼠中，这种表达水平的降低导致T细胞对胰岛素的反应。这项研究是为了检查胸腺胰岛素表达是否受到与β细胞相同的代谢刺激或不同输入（可能是免疫性质的）的调节。腹腔注射葡萄糖后，在体内观察小鼠胸腺Ins2 mRNA的变化。我们还研究了高葡萄糖浓度对表达胰岛素的骨髓胸腺上皮细胞系（mTECs）克隆中Ins2 mRNA的影响。同样的体外系统被用来评估ifn - γ和细胞间接触胸腺细胞在共培养中的影响。葡萄糖负荷后，胰腺中的Ins2 mRNA显著增加，但胸腺中的Ins2 mRNA保持不变。此外，体外用ifn - γ（一种参与T细胞阴性选择的细胞因子）刺激表达胰岛素的mTECs，尽管Aire的表达增加，但胰岛素表达水平降低。最后，mtec与胸腺细胞共培养导致Aire和胰岛素表达上调。我们得出结论，胸腺中胰岛素转录的调节不依赖于代谢刺激，而可能是在细胞因子和淋巴样细胞的细胞间相互作用的控制下。这种调节并不总是与Aire（一个非特异性的主开关）协调，这表明胰岛素的特异性机制。
The expression of tissue-specific self-antigens in the thymus is essential for self-tolerance. Genetic susceptibility to type 1 diabetes correlates inversely with thymic insulin expression and, in mice, lowered levels of this expression result in T cell responses against insulin. This study was undertaken to examine whether thymic insulin expression is regulated by the same metabolic stimuli as in beta cells or by different inputs, possibly of an immune nature.Ins2 mRNA changes in mouse thymus were evaluated in vivo, following intraperitoneal glucose injection. We also examined the effect of a high glucose concentration on Ins2 mRNA in clones of insulin-expressing medullary thymus epithelial cell lines (mTECs). The same in vitro system was used to evaluate the effect of IFN-gamma and cell-to-cell contact with thymocytes in co-culture.Ins2 mRNA was significantly increased in the pancreas following a glucose load, but remained unchanged in the thymus. Furthermore, stimulation of insulin-expressing mTECs in vitro with IFN-gamma, a cytokine involved in T cell negative selection, decreased levels of insulin expression even though expression of Aire was increased. Last, co-culture of mTECs with thymocytes resulted in an upregulation of both Aire and insulin expression.We conclude that regulation of insulin transcription in the thymus is not dependent on metabolic stimuli but it may, instead, be under the control of cytokines and cell-to-cell interactions with lymphoid cells. That this regulation is not always coordinated with that of Aire, a non-specific master switch, suggests insulin-specific mechanisms.