Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans
Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans
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DOI：
10.1182/blood-2012-05-432336
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发表时间：
2013-02-28
期刊：
影响因子：
20.3
通讯作者：
Lu, Nick Z.
中科院分区：
文献类型：
--
作者：
Cao, Yun;Bender, Ingrid K.;Lu, Nick Z.
虽然糖皮质激素是一类非常重要的抗炎和免疫抑制剂，但它们在树突状细胞（dc）中的作用尚不清楚。我们发现，地塞米松（一种有效的糖皮质激素）在健康小鼠、实验性气道炎症小鼠和体外骨髓源性dc中选择性地诱导成熟dc细胞凋亡，而非未成熟dc细胞凋亡。不同的糖皮质激素受体（GR）翻译异构体在未成熟和成熟的DC中表达，可能有助于DC成熟阶段特异性的糖皮质激素敏感性。在未成熟的dc中，GR-D亚型是主要亚型，而在成熟的dc中，促凋亡的GR-A亚型是主要亚型。未成熟dc中GR- a异构体的异位表达增加了糖皮质激素的敏感性，而选择性GR拮抗剂RU486抑制了成熟dc的糖皮质激素敏感性。此外，在人类单核细胞来源的树突状细胞中也观察到未成熟和成熟小鼠树突状细胞中GR亚型的不同表达模式。这些研究表明，糖皮质激素可能通过GR翻译异构体的差异表达来保护未成熟的dc，抑制成熟的dc和炎症。
Although glucocorticoids are a profoundly important class of anti-inflammatory and immunosuppressive agents, their actions in dendritic cells (DCs) are not well understood. We found that dexamethasone, a potent glucocorticoid, selectively induced apoptosis in mature, but not in immature, DCs in healthy mice, in mice with experimental airway inflammation, and in vitro in bone marrow-derived DCs. Distinct glucocorticoid receptor (GR) translational isoforms expressed in immature and mature DCs probably contribute to the DC maturational stage-specific glucocorticoid sensitivity. The GR-D isoforms were the predominant isoforms in immature DCs, whereas the proapoptotic GR-A isoform was the main isoform in mature DCs. Ectopic expression of the GR-A isoform in immature DCs increased glucocorticoid sensitivity and RU486, a selective GR antagonist, inhibited the glucocorticoid sensitivity of mature DCs. Furthermore, the distinct expression pattern of GR isoforms in immature and mature murine DCs was also observed in human monocyte-derived DCs. These studies suggest that glucocorticoids may spare immature DCs and suppress mature DCs and inflammation via differential expression of GR translational isoforms.