Department of Bioscience and Biotechnology, Indian Institute of Technology Kharagpur, West Bengal, India.
J Immunol. 2024 Sep 15;213(6):831-842. doi: 10.4049/jimmunol.2400078.
Calcitriol, the bioactive form of vitamin D, exerts its biological functions by binding to its cognate receptor, the vitamin D receptor (VDR). The indicators of the severity of allergies and asthma have been linked to low vitamin D levels. However, the role of calcitriol in regulating IL-4 and IL-13, two cytokines pivotal to allergic inflammation, remained unclear. Our study observed diminished IL-4 and IL-13 secretion in murine and human Th2 cells treated with calcitriol. In murine Th2 cells, Gata3 expression was attenuated by calcitriol. However, the expression of the transcriptional repressor Gfi1, too, was attenuated in the presence of calcitriol. Ectopic expression of either Gfi1 or VDR impaired the secretion of IL-13 in Th2 cells. In murine Th2 cells, VDR interacted with Gata3 but not Gfi1. Gfi1 significantly impaired Il13 promoter activation, which calcitriol failed to restore. Conversely, calcitriol augmented Gfi1 recruitment to the Il13 promoter. Ecr, a conserved region between these two genes, which enhanced the transactivation of Il4 and Il13 promoters, is essential for calcitriol-mediated suppression of both the genes. Calcitriol augmented the recruitment of VDR to the Il13 promoter and Ecr regions. Gata3 recruitment was significantly impaired at the Il13 and Ecr loci in the presence of calcitriol but increased at the Il4 promoter. Furthermore, the recruitment of the histone deacetylase HDAC1 was universally increased at the promoters of Il4, Il13, and Ecr when calcitriol was present. Together, our data clearly elucidate that calcitriol modulates VDR, Gata3, and Gfi1 to suppress IL-4 and IL-13 production in Th2 cells.
钙三醇，维生素 D 的生物活性形式，通过与其同源受体维生素 D 受体 (VDR) 结合发挥其生物学功能。过敏和哮喘的严重程度指标与维生素 D 水平低有关。然而，钙三醇在调节白细胞介素-4 (IL-4) 和白细胞介素-13 (IL-13) 中的作用，这两种细胞因子是过敏炎症的关键，仍然不清楚。我们的研究观察到，钙三醇处理的鼠和人 Th2 细胞中 IL-4 和 IL-13 的分泌减少。在鼠 Th2 细胞中，钙三醇减弱了 Gata3 的表达。然而，在钙三醇存在的情况下，转录抑制因子 Gfi1 的表达也减弱了。Gfi1 或 VDR 的异位表达均损害了 Th2 细胞中 IL-13 的分泌。在鼠 Th2 细胞中，VDR 与 Gata3 相互作用，但不与 Gfi1 相互作用。Gfi1 显著抑制 Il13 启动子的激活，而钙三醇不能恢复。相反，钙三醇增强了 Gfi1 向 Il13 启动子的募集。这两个基因之间的 Ecr 保守区域增强了 Il4 和 Il13 启动子的反式激活，对于钙三醇介导的这两个基因的抑制是必需的。钙三醇增强了 VDR 向 Il13 启动子和 Ecr 区域的募集。在钙三醇存在的情况下，Gata3 在 Il13 和 Ecr 基因座的募集显著受损，但在 Il4 启动子时增加。此外，当钙三醇存在时，组蛋白去乙酰化酶 HDAC1 的募集在 Il4、Il13 和 Ecr 启动子上普遍增加。总之，我们的数据清楚地阐明了钙三醇通过调节 VDR、Gata3 和 Gfi1 来抑制 Th2 细胞中 IL-4 和 IL-13 的产生。
