Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
J Exp Med. 2019 Feb 4;216(2):384-406. doi: 10.1084/jem.20180595. Epub 2019 Jan 23.
Glucocorticoids remain the most widely used immunosuppressive and anti-inflammatory drugs, yet substantial gaps exist in our understanding of glucocorticoid-mediated immunoregulation. To address this, we generated a pathway-level map of the transcriptional effects of glucocorticoids on nine primary human cell types. This analysis revealed that the response to glucocorticoids is highly cell type dependent, in terms of the individual genes and pathways affected, as well as the magnitude and direction of transcriptional regulation. Based on these data and given their importance in autoimmunity, we conducted functional studies with B cells. We found that glucocorticoids impair upstream B cell receptor and Toll-like receptor 7 signaling, reduce transcriptional output from the three immunoglobulin loci, and promote significant up-regulation of the genes encoding the immunomodulatory cytokine IL-10 and the terminal-differentiation factor BLIMP-1. These findings provide new mechanistic understanding of glucocorticoid action and emphasize the multifactorial, cell-specific effects of these drugs, with potential implications for designing more selective immunoregulatory therapies.
糖皮质激素仍然是最广泛使用的免疫抑制和抗炎药物，但我们对糖皮质激素介导的免疫调节的理解还存在很大差距。为了解决这个问题，我们生成了一个关于糖皮质激素对九种主要人类细胞类型转录效应的途径水平图谱。这项分析表明，糖皮质激素的反应在个体基因和途径的影响、转录调控的幅度和方向上，在很大程度上取决于细胞类型。基于这些数据，考虑到它们在自身免疫中的重要性，我们对 B 细胞进行了功能研究。我们发现，糖皮质激素会损害 B 细胞受体和 Toll 样受体 7 信号的上游，减少三个免疫球蛋白基因座的转录输出，并显著上调编码免疫调节细胞因子 IL-10 和终末分化因子 BLIMP-1 的基因。这些发现为糖皮质激素作用的机制提供了新的理解，并强调了这些药物的多因素、细胞特异性效应，这可能对设计更具选择性的免疫调节治疗具有重要意义。
