Varricchio Lilian, Migliaccio Anna Rita
Tisch Cancer Institute, Mount Sinai School of Medicine New York, NY 10029, USA.
Tisch Cancer Institute, Mount Sinai School of Medicine New York, NY 10029, USA ; Istituto Superiore di Sanita' Viale Regina Elena 299 Italy.
Am J Blood Res. 2014 Dec 15;4(2):53-72. eCollection 2014.
Glucocorticoids are endogenous steroid hormones that regulate several biological functions including proliferation, differentiation and apoptosis in numerous cell types in response to stress. Synthetic glucocorticoids, such as dexamethasone (Dex) are used to treat a variety of diseases ranging from allergy to depression. Glucocorticoids exert their effects by passively entering into cells and binding to a specific Glucocorticoid Receptor (GR) present in the cytoplasm. Once activated by its ligand, GR may elicit cytoplasmic (mainly suppression of p53), and nuclear (regulation of transcription of GR responsive genes), responses. Human GR is highly polymorphic and may encode > 260 different isoforms. This polymorphism is emerging as the leading cause for the variability of phenotype and response to glucocorticoid therapy observed in human populations. Studies in mice and clinical observations indicate that GR controls also the response to erythroid stress. This knowledge has been exploited in-vivo by using synthetic GR agonists for treatment of the erythropoietin-refractory congenic Diamond Blackfan Anemia and in-vitro to develop culture conditions that may theoretically generate red cells in numbers sufficient for transfusion. However, the effect exerted by GR polymorphism on the variability of the phenotype of genetic and acquired erythroid disorders observed in the human population is still poorly appreciated. This review will summarize current knowledge on the biological activity of GR and of its polymorphism in non-hematopoietic diseases and discuss the implications of these observations for erythropoiesis.
糖皮质激素是内源性甾体激素，可调节多种生物学功能，包括在多种细胞类型中对应激作出反应的增殖、分化和凋亡。合成糖皮质激素，如地塞米松（Dex），被用于治疗从过敏到抑郁症等多种疾病。糖皮质激素通过被动进入细胞并与细胞质中存在的特定糖皮质激素受体（GR）结合来发挥其作用。一旦被其配体激活，GR可能引发细胞质反应（主要是抑制p53）和细胞核反应（调节GR反应基因的转录）。人类GR具有高度多态性，可能编码超过260种不同的异构体。这种多态性正成为人类群体中观察到的表型变异性和对糖皮质激素治疗反应的主要原因。对小鼠的研究和临床观察表明，GR也控制对红细胞应激的反应。这一知识已在体内通过使用合成GR激动剂治疗促红细胞生成素难治性先天性钻石黑范贫血得到应用，并在体外用于开发理论上可产生足以用于输血数量红细胞的培养条件。然而，GR多态性对人类群体中观察到的遗传性和获得性红细胞疾病表型变异性的影响仍未得到充分认识。本综述将总结目前关于GR及其多态性在非造血疾病中的生物学活性的知识，并讨论这些观察结果对红细胞生成的影响。
