Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy.
Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy.
复制标题
DOI：
10.1016/j.pharmthera.2016.06.002
复制
发表时间：
2016-09
影响因子：
13.5
通讯作者：
Moliki, Johnson M.
中科院分区：
文献类型：
--
作者：
Hapgood, Janet P.;Avenant, Chanel;Moliki, Johnson M.
药理剂量的糖皮质激素(GCs)通过糖皮质激素受体(GR)抑制炎症和免疫功能，仍然是治疗炎症和免疫疾病的最有效的治疗方法。由于许多接受GC治疗的患者表现出GC耐药和严重的副作用，因此许多研究集中在开发更具选择性的GC和联合治疗，具有更强的抗炎效力。GCS通过与细胞质GR结合来介导其经典的基因组转录效应，然后通过GR与DNA的直接结合或与其他转录因子的连接来调控靶基因的核转位和转录。然而，最近的证据表明，GR介导的反应要复杂得多，涉及多种并行机制，在没有GCs和存在GCs的情况下，整合来自其他受体的同时信号，以转移靶细胞对GCs的敏感性。细胞应激水平、免疫激活状态或细胞周期阶段可能是决定GC敏感性和GC反应性以及GR和GR水平的亚细胞定位的关键。以GR信号为靶点或作为附加疗法的新药开发的核心是深入了解GC非依赖性GR脱敏、启动和激活未连接GR的分子机制，以及与其他信号通路的协同和串扰。这篇综述将讨论目前关于这些主题的现有信息及其与免疫疗法的相关性，以及确定未回答的问题和未来的研究领域。
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 focussed 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 signalling 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 signalling 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.
登录
查看更多内容
糖皮质激素受体在巨噬细胞中协调转录因子主导的调节网络。
影响因子：
4.4
作者：
Chinenov Y;Coppo M;Gupte R;Sacta MA;Rogatsky I
通讯作者：
Rogatsky I
影响因子：
4.1
作者：
Burd, Craig J.;Archer, Trevor K.
通讯作者：
Archer, Trevor K.
DOI：
10.1124/jpet.114.221226
发表时间：
2015-05-01
影响因子：
3.5
作者：
Boger, Elin;Ewing, Par;Friden, Markus
通讯作者：
Friden, Markus
影响因子：
20.3
作者：
Cao, Yun;Bender, Ingrid K.;Lu, Nick Z.
通讯作者：
Lu, Nick Z.
影响因子：
29.4
作者：
Bergann, Theresa;Zeissig, Sebastian;Schulzke, Joerg-Dieter
通讯作者：
Schulzke, Joerg-Dieter