Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus
Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus
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DOI：
10.4049/jimmunol.166.6.4216
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发表时间：
2001-03-15
影响因子：
4.4
通讯作者：
Tsokos, GC
中科院分区：
文献类型：
--
作者：
Solomou, EE;Juang, YT;Tsokos, GC
系统性红斑狼疮（SLE）是一种多因素的自身免疫性疾病，其特征是多种细胞和生化畸变，包括IL-2产生减少。在这里，我们表明，从未刺激的SLE T细胞的核提取物，从正常T细胞的提取物不同，表达磷酸化cAMP反应元件调节剂（p-CREM），结合IL-2启动子的-180位点的量增加。来自刺激的正常T细胞的核提取物显示磷酸化cAMP反应元件结合蛋白（p-CREB）与IL-2启动子-180位点的结合增加，而来自刺激的SLE T细胞的核提取物主要显示p-CREM和p-CREB结合减少。在SLE T细胞中，p-CREM与转录辅激活因子CREB结合蛋白和p300结合，p-CREM表达增加与IL-2产生减少相关，由-180位点驱动的报告基因在正常T细胞中转录增强，而在SLE T细胞中被抑制。这些实验表明转录抑制是SLE T细胞产生IL-2减少的原因。
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by diverse cellular and biochemical aberrations, including decreased production of IL-2. Here we show that nuclear extracts from unstimulated SLE T cells, unlike extracts from normal T cells, express increased amounts of phosphorylated cAMP-responsive element modulator (p-CREM) that binds the -180 site of the IL-2 promoter. Nuclear extracts from stimulated normal T cells display increased binding of phosphorylated cAMP-responsive element binding protein (p-CREB) to the -180 site of the IL-2 promoter, whereas nuclear extracts from stimulated SLE T cells display primarily p-CREM and decreased p-CREB binding. In SLE T cells, p-CREM bound to the transcriptional coactivators, CREB binding protein and p300, Increased expression of p-CREM correlated with decreased production of IL-2, The transcription of a reporter gene driven by the -180 site was enhanced in normal T cells, but was suppressed in SLE T cells. These experiments demonstrate that transcriptional repression is responsible for the decreased production of IL-2 by SLE T cells.