糖皮质激素通过重塑巨核细胞转录组来调节血小板生成。
Glucocorticoids regulate thrombopoiesis by remodeling the megakaryocyte transcriptome.
机构信息
Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
出版信息
J Thromb Haemost. 2023 Nov;21(11):3207-3223. doi: 10.1016/j.jtha.2023.06.012. Epub 2023 Jun 17.
BACKGROUND
Glucocorticoids are widely known for their immunomodulatory action. Their synthetic analogs are used to treat several autoimmune diseases, including immune thrombocytopenia. However, their efficacy and mechanisms of action in immune thrombocytopenia are not fully understood.
OBJECTIVES
To investigate the mechanism of glucocorticoid actions on platelet production.
METHODS
The actions of glucocorticoids on platelet production were studied combining in vivo, ex vivo and in vitro approaches.
RESULTS
Dexamethasone reduced bleeding in mice and rapidly increased circulating young platelet counts. In vitro glucocorticoid treatment stimulated proplatelet formation by megakaryocytes and platelet-like particle release. This effect was blocked by glucocorticoid receptor antagonist RU486, indicating a glucocorticoid receptor-dependent mechanism. Genome-wide analysis revealed that dexamethasone regulates the expression of >1000 genes related to numerous cellular functions, including predominant cytoplasm and cytoskeleton reorganization. Dexamethasone and other glucocorticoids induced the expression of Gda (the gene encoding guanine deaminase), which has been reported to have a role in dendrite development. Inhibition of guanine deaminase enzymatic activity blocked dexamethasone stimulation of proplatelet formation, implicating a critical role for this enzyme in glucocorticoid-mediated platelet production.
CONCLUSION
Our findings identify glucocorticoids as new regulators of thrombopoiesis.
背景
糖皮质激素以其免疫调节作用而广为人知。它们的合成类似物被用于治疗多种自身免疫性疾病，包括免疫性血小板减少症。然而，它们在免疫性血小板减少症中的疗效和作用机制尚不完全清楚。
目的
研究糖皮质激素对血小板生成的作用机制。
方法
结合体内、体外和体外方法研究糖皮质激素对血小板生成的作用。
结果
地塞米松可减少小鼠的出血，并迅速增加循环中的年轻血小板计数。糖皮质激素治疗可刺激巨核细胞形成血小板样颗粒和血小板样颗粒释放。该作用被糖皮质激素受体拮抗剂 RU486 阻断，表明这是一种糖皮质激素受体依赖性机制。全基因组分析显示，地塞米松调节与多种细胞功能相关的 >1000 个基因的表达，包括主要的细胞质和细胞骨架重排。地塞米松和其他糖皮质激素诱导 Gda（编码鸟嘌呤脱氨酶的基因）的表达，该基因已被报道在树突发育中起作用。鸟嘌呤脱氨酶酶活性的抑制阻断了地塞米松对血小板样颗粒形成的刺激，表明该酶在糖皮质激素介导的血小板生成中起着关键作用。
结论
我们的研究结果确定了糖皮质激素是新的血小板生成调节剂。
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