Solomou E E, Juang Y T, Gourley M F, Kammer G M, Tsokos G C
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
J Immunol. 2001 Mar 15;166(6):4216-22. doi: 10.4049/jimmunol.166.6.4216.
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.
系统性红斑狼疮（SLE）是一种多因素自身免疫性疾病，其特征为多种细胞和生化异常，包括白细胞介素-2（IL-2）产生减少。我们在此表明，未受刺激的SLE T细胞的核提取物与正常T细胞的提取物不同，表达量增加的磷酸化环磷酸腺苷反应元件调节剂（p-CREM），其与IL-2启动子的-180位点结合。受刺激的正常T细胞的核提取物显示磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB）与IL-2启动子的-180位点的结合增加，而受刺激的SLE T细胞的核提取物主要显示p-CREM且p-CREB结合减少。在SLE T细胞中，p-CREM与转录共激活因子、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的转录在正常T细胞中增强，但在SLE T细胞中受到抑制。这些实验表明转录抑制是SLE T细胞中IL-2产生减少的原因。
