Early lymphoid progenitors in mouse and man are highly sensitive to glucocorticoids
Early lymphoid progenitors in mouse and man are highly sensitive to glucocorticoids
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DOI：
10.1093/intimm/dxh230
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发表时间：
2005-05-01
影响因子：
4.4
通讯作者：
Kincade, PW
中科院分区：
文献类型：
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作者：
Igarashi, H;Medina, KL;Kincade, PW
糖皮质激素被广泛用于抗炎治疗，可能有助于淋巴生成的正常调节。这项研究利用了关于小鼠和人类早期淋巴生成的新信息，以准确地确定哪些细胞类型是激素敏感的。在地塞米松治疗的小鼠中，周期B系前体细胞被耗尽，而成熟的、不分裂的CD45R(Hi)CD19(Hi)淋巴细胞、髓系祖细胞和干细胞在移植时没有产生淋巴细胞的潜力。谱系标记阴性(LIN(-))、IL-7R(+)、Flk-2(+)前淋巴细胞也下降，但速度不如早期LIN(-)c-kit(Hi)SCA-1(Hi)部分中的末端脱氧核苷酸转移酶阳性细胞。使用人MU转基因小鼠和重组激活基因1(RAG1)/绿色荧光蛋白敲入动物，在相同的LIN(-)c-kit(Hi)SCA-1(Hi)亚群中鉴定出具有早期淋巴系祖细胞(ELP)额外特性的激素敏感细胞。此外，在骨髓和脾中，最近有RAG1表达史的细胞比成熟的淋巴细胞对糖皮质激素更敏感。携带人类bcl2转基因小鼠的淋巴细胞前体细胞不受地塞米松治疗的保护。然而，从野生型或bcl2转基因小鼠分离的祖细胞在无基质细胞培养中对激素直接敏感，这表明额外的因素必须决定对糖皮质激素的易感性。在去肾上腺或RU486处理的小鼠的骨髓中，发现B系淋巴细胞前体异常升高。这表明糖皮质激素正常情况下可能有助于淋巴生成的稳定状态调节。最后，平行研究表明，人类淋巴生成的最早事件在糖皮质激素治疗期间容易受到伤害。
Glucocorticoids are extensively used in anti-inflammatory therapy and may contribute to the normal regulation of lymphopoiesis. This study utilized new information about the early stages of lymphopoiesis in mouse and man to determine precisely which cell types are hormone sensitive. Cycling B lineage precursors were depleted in dexamethasone-treated mice, while mature, non-dividing CD45R(Hi) CD19(Hi) lymphocytes, myeloid progenitors and stem cells with the potential for lymphocyte generation on transplantation were spared. Lineage marker-negative (Lin(-)) IL-7R(+) Flk-2(+) pro-lymphocytes also declined, but not as rapidly as the terminal deoxynucleotidyl transferase-positive cells within an early Lin(-) c-kit(Hi) Sca-1(Hi) fraction of bone marrow. Hormone-sensitive cells with additional properties of early lymphoid progenitors (ELP) were identified within the same Lin(-) c-kit(Hi) Sca-1(Hi) subset using human mu transgenic mice and recombination-activating gene 1 (RAG1)/green fluorescent protein knock-in animals. Furthermore, cells with a recent history of RAG1 expression were more glucocorticoid sensitive than mature lymphocytes in marrow and spleen. Lymphocyte progenitors in mice bearing a human bcl-2 transgene were protected from dexamethasone treatment. However, isolated progenitors from either wild-type or bcl-2 transgenic mice were directly sensitive to the hormone in stromal cell-free cultures, suggesting that additional factors must determine vulnerability to glucocorticoids. B lineage lymphocyte precursors were found to be abnormally elevated in the bone marrow of adrenalectomized or RU486-treated mice. This suggests that glucocorticoids may normally contribute to steady-state regulation of lymphopoiesis. Finally, parallel studies revealed that the earliest events in human lymphopoiesis are susceptible to injury during glucocorticoid therapy.