Hapgood Janet P, Avenant Chanel, Moliki Johnson M
Department of Molecular and Cell Biology, University of Cape Town, Private Bag X3, Rondebosch, 7700, South Africa.
Department of Molecular and Cell Biology, University of Cape Town, Private Bag X3, Rondebosch, 7700, South Africa.
Pharmacol Ther. 2016 Sep;165:93-113. doi: 10.1016/j.pharmthera.2016.06.002. Epub 2016 Jun 8.
Pharmacological doses of glucocorticoids (GCs), acting via the glucocorticoid receptor (GR) to repress inflammation and immune function, remain the most effective therapy in the treatment of inflammatory and immune diseases. Since many patients on GC therapy exhibit GC resistance and severe side-effects, much research is focused on developing more selective GCs and combination therapies, with greater anti-inflammatory potency. GCs mediate their classical genomic transcriptional effects by binding to the cytoplasmic GR, followed by nuclear translocation and modulation of transcription of target genes by direct DNA binding of the GR or its tethering to other transcription factors. Recent evidence suggests, however, that the responses mediated by the GR are much more complex and involve multiple parallel mechanisms integrating simultaneous signals from other receptors, both in the absence and presence of GCs, to shift the sensitivity of a target cell to GCs. The level of cellular stress, immune activation status, or the cell cycle phase may be crucial for determining GC sensitivity and GC responsiveness as well as subcellular localization of the GR and GR levels. Central to the development of new drugs that target GR signaling alone or as add-on therapies, is an in-depth understanding of the molecular mechanisms of GC-independent GR desensitization, priming and activation of the unliganded GR, as well as synergy and cross-talk with other signaling pathways. This review will discuss the information currently available on these topics and their relevance to immunotherapy, as well as identify unanswered questions and future areas of research.
药理剂量的糖皮质激素（GCs）通过糖皮质激素受体（GR）发挥作用，抑制炎症和免疫功能，仍然是治疗炎症和免疫性疾病最有效的疗法。由于许多接受GC治疗的患者表现出GC抵抗和严重的副作用，大量研究集中在开发更具选择性的GCs和联合疗法，以提高抗炎效力。GCs通过与细胞质中的GR结合介导其经典的基因组转录效应，随后发生核转位，并通过GR直接结合DNA或与其他转录因子结合来调节靶基因的转录。然而，最近的证据表明，GR介导的反应要复杂得多，涉及多种平行机制，在有无GCs的情况下整合来自其他受体的同时信号，以改变靶细胞对GCs的敏感性。细胞应激水平、免疫激活状态或细胞周期阶段对于确定GC敏感性、GC反应性以及GR的亚细胞定位和GR水平可能至关重要。开发单独靶向GR信号或作为附加疗法的新药的核心是深入了解不依赖GC的GR脱敏、未结合配体的GR的启动和激活以及与其他信号通路的协同和相互作用的分子机制。本综述将讨论目前关于这些主题的可用信息及其与免疫治疗的相关性，并确定未解决的问题和未来的研究领域。
