Ohl Kim, Wiener Anastasia, Lippe Ralph, Schippers Angela, Zorn Carolin, Roth Johannes, Wagner Norbert, Tenbrock Klaus
Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany.
Institute of Immunology, University of Münster , Münster , Germany.
Front Immunol. 2016 Dec 19;7:618. doi: 10.3389/fimmu.2016.00618. eCollection 2016.
The cAMP-responsive element modulator alpha (CREMα) plays a role in autoimmunity and, in particular, in systemic lupus erythematosus. CREMα negatively regulates IL-2 transcription and activates IL-17 expression by direct transcriptional mechanisms. To understand the role of CREM in autoimmunity, we recently generated a mouse with a transgenic overexpression of CREMα selectively in T cells. This mouse is characterized by enhanced IL-17 and IL-21 expression. We, herein, dissect the transcriptional mechanisms of enhanced IL-21 transcription in these mice. T cells of CREMα transgenic mice display an enhanced binding of CREMα to the CD3ζ chain promoter resulting in decreased CD3ζ chain expression. This is accompanied by a decreased excitation threshold and enhanced Ca influx, which is known to induce IL-21 expression NFATc2 activation. However, CREMα directly binds to cAMP-response element (CRE) half-site within the promoter, which results in enhanced promoter activity shown by promoter reporter assays. CREMα-induced IL-21 transcription is not abrogated in the presence of cyclosporine A but depends on an intact CRE site within the IL-21 promoter, which suggests that CREM largely enhances IL-21 expression by direct transcriptional regulation. IL-21 transcription is critical for IL-17 generation in these mice, since IL-21 receptor blockade downregulates IL-17 transcription to wild-type levels. Finally, this is of functional relevance since CREMα transgenic mice display enhanced disease activity in dextran sodium sulfate-induced colitis accompanied by higher local IL-21 expression. Thus, we describe two novel mechanisms of CREMα-dependent IL-21 transcription. Since T cells of systemic lupus erythematosus patients are characterized by enhanced IL-21 transcription, this might also be of functional relevance in humans.
环磷酸腺苷反应元件调节因子α（CREMα）在自身免疫中发挥作用，尤其是在系统性红斑狼疮中。CREMα通过直接转录机制负向调节白细胞介素-2（IL-2）的转录并激活白细胞介素-17（IL-17）的表达。为了解CREM在自身免疫中的作用，我们最近培育出一种在T细胞中选择性过表达CREMα的转基因小鼠。这种小鼠的特征是IL-17和IL-21表达增强。在此，我们剖析了这些小鼠中IL-21转录增强的转录机制。CREMα转基因小鼠的T细胞显示CREMα与CD3ζ链启动子的结合增强，导致CD3ζ链表达降低。这伴随着兴奋阈值降低和钙离子内流增强，已知这会诱导IL-21表达和活化T细胞核因子c2（NFATc2）。然而，CREMα直接结合到启动子内的环磷酸腺苷反应元件（CRE）半位点，这通过启动子报告基因检测显示启动子活性增强。在存在环孢素A的情况下，CREMα诱导的IL-21转录并未被消除，但依赖于IL-21启动子内完整的CRE位点，这表明CREM主要通过直接转录调控增强IL-21的表达。IL-21转录对于这些小鼠中IL-17的产生至关重要，因为阻断IL-21受体可将IL-17转录下调至野生型水平。最后，这具有功能相关性，因为CREMα转基因小鼠在葡聚糖硫酸钠诱导的结肠炎中表现出增强的疾病活性，伴有更高的局部IL-21表达。因此，我们描述了两种依赖CREMα的IL-21转录的新机制。由于系统性红斑狼疮患者的T细胞以IL-21转录增强为特征，这在人类中可能也具有功能相关性。
