Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Mol Med. 2012 May 9;18(1):370-8. doi: 10.2119/molmed.2011.00506.
Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex multifactorial pathogenesis. T lymphocytes play a critical role in disease pathogenesis and display abnormal gene expression and poor interleukin (IL)-2 production. We previously showed that the expression of the transcriptional repressor cyclic AMP response element modulator α (CREMα) is increased in SLE T cells and contributes to reduced IL-2 production. Although estrogen is implicated in the onset and exacerbation of SLE, the precise nature of molecular events regulated by estrogen in immune cell function is not well understood. Here, we asked whether estrogen regulates the expression of CREMα in human T lymphocytes. We show that exposure of human T cells to 17-β-estradiol leads to a dose-dependent increase in CREMα mRNA expression, and this increase appears to be mediated through the estrogen receptors α and β. We show that the increased expression of CREMα is due to increased transcriptional activity of the CREM promoter and is mediated by increased expression and binding of the Sp1 transcriptional activator. We further show that estrogen treatment leads to a dose-dependent decrease in IL-2 mRNA and cytokine production by T cells. Finally, the effect of β-estradiol on CREMα is observed more frequently in T cells from women than from men. We conclude that estrogen can modulate the expression of CREMα and lead to IL-2 suppression in human T lymphocytes, thus revealing a molecular link between hormones and the immune system in SLE.
系统性红斑狼疮（SLE）是一种具有复杂多因素发病机制的自身免疫性疾病。T 淋巴细胞在疾病发病机制中起关键作用，表现为异常基因表达和白细胞介素（IL）-2 产生减少。我们之前的研究表明，转录抑制因子环磷酸腺苷反应元件调节剂α（CREMα）的表达在 SLE T 细胞中增加，并导致 IL-2 产生减少。尽管雌激素与 SLE 的发病和恶化有关，但雌激素在免疫细胞功能中调节的分子事件的确切性质尚不清楚。在这里，我们询问雌激素是否调节人 T 淋巴细胞中 CREMα的表达。我们表明，17-β-雌二醇暴露于人 T 细胞中会导致 CREMα mRNA 表达的剂量依赖性增加，并且这种增加似乎是通过雌激素受体 α 和 β 介导的。我们表明，CREMα 的表达增加是由于 CREM 启动子的转录活性增加，并且是通过 Sp1 转录激活剂的表达和结合增加介导的。我们进一步表明，雌激素处理导致 T 细胞中 IL-2 mRNA 和细胞因子产生的剂量依赖性降低。最后，β-雌二醇对 CREMα 的作用在女性 T 细胞中比男性 T 细胞中更为常见。我们得出结论，雌激素可以调节 CREMα 的表达并导致人 T 淋巴细胞中 IL-2 的抑制，从而揭示了 SLE 中激素与免疫系统之间的分子联系。
