Regulatory mechanism of glucocorticoid for B lymphocyte activation and development

糖皮质激素对B淋巴细胞活化和发育的调节机制

• 批准号: 14570282
• 负责人: IGARASHI Hideya
• 金额: $ 2.24万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570282/
• 关键词: glucocorticoid; B cell activation; B cell development; グルココルチコイド; GR; G5PR; フォスファターゼ; PP2A; PP5; GANP

Patterns of lymphoid progenitor deficiency in some patient marrow specimens suggested these cells might be affected by anti-inflammatory therapy. Supportive evidence for this possibility was obtained with culture and chimeric animal experiments, where human lymphoid progenitors were preferentially depressed by exposure to glucocorticoids. Studies conducted with dexamethasone treated mice revealed selective depletion of cycling B lineage precursors. In contrast, mature, non-dividing CD45R^<Hi> CD19^<Hi> lymphocytes, myeloid progenitors and stem cells with the potential for lymphocyte generation on transplantation were spared. Lin^-IL-7R^+ Flk-2^+ pro-lymphocytes also declined, but not as rapidly as the TdT^+ cells within an early Lin^-c-kit^<Hi> Sca-1^<Hi> fraction of bone marrow. Hormone sensitive cells with additional properties of early lymphocyte progenitors were identified within the same Lin^-c-kit^<Hi> Sca-1^<Hi> subset using human m transgenic mice and RAG1/GFP 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. B lineage lymphocyte precursors were found to be abnormally elevated in bone marrow of adrenalectomized or RU486 treated mice. This suggests that glucocorticoids may normally contribute to steady-state regulation of lymphopoiesis. These findings are informative about means for controlling lymphocyte production in central lymphoid organs and suggest experimental approaches for determining the sequence of early differentiation events.

一些患者骨髓标本中淋巴祖细胞缺乏的模式表明这些细胞可能受到抗炎治疗的影响。通过培养和嵌合动物实验获得了这种可能性的支持证据，其中人类淋巴祖细胞优先因暴露于糖皮质激素而受到抑制。对地塞米松治疗的小鼠进行的研究表明，循环 B 谱系前体细胞被选择性耗尽。相反，成熟的、不分裂的CD45R^<Hi>CD19^<Hi>淋巴细胞、骨髓祖细胞和在移植时具有产生淋巴细胞潜力的干细胞则幸免于难。 Lin^-IL-7R^+ Flk-2^+ 前淋巴细胞也下降，但不如早期 Lin^-c-kit^<Hi> Sca-1^<Hi> 部分中的 TdT^+ 细胞下降得那么快骨髓。使用人转基因小鼠和 RAG1/GFP 敲入动物在相同的 Lin^-c-kit^<Hi> Sca-1^<Hi> 子集中鉴定出具有早期淋巴细胞祖细胞附加特性的激素敏感细胞。此外，近期有 RAG1 表达史的细胞比骨髓和脾脏中的成熟淋巴细胞对糖皮质激素更敏感。携带人类 bcl-2 转基因的小鼠的淋巴细胞祖细胞免受地塞米松治疗。然而，来自野生型或 bcl-2 转基因小鼠的分离祖细胞对无基质细胞培养物中的激素直接敏感。发现肾上腺切除或 RU486 治疗小鼠的骨髓中 B 系淋巴细胞前体异常升高。这表明糖皮质激素通常可能有助于淋巴细胞生成的稳态调节。这些发现为控制中央淋巴器官中淋巴细胞产生的方法提供了信息，并提出了确定早期分化事件序列的实验方法。

项目成果

Takafumi Yokota: "Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins"J. Clin. Invest.. 109. 1303-1310 (2002)

Takafumi Yokota：“通过脂联素和前列腺素对骨髓培养物中脂肪细胞形成的旁分泌调节”J。

Takafumi Yokota, C.S.Reddy Meka, Taku Kouro, K.L.Medina, Hideya Igarashi, Masahiko Takahashi, Kenji Oritani, Tohru Funahashi, Yashiaki Tomiyama, Yuji Matsuzawa, Paul W.Kincade: "Adiponectin, a fat cell product, influences the earliest lymphocyte precursor

Takafumi Yokota、C.S.Reddy Meka、Taku Kouro、K.L.Medina、Hideya Igarashi、Masahiko Takahashi、Kenji Oritani、Tohru Funahashi、Yashiaki Tomiyama、Yuji Matsuzawa、Paul W.Kincade：“脂联素是一种脂肪细胞产物，影响最早的淋巴细胞前体

Paul W.Kincade: "Lymphoid lineage cells in adult murine bone marrow diverge from those of other blood cells at an early, hormone sensitive stage"Semin Immunol.. 14. 385-394 (2002)

Paul W.Kincade：“成年小鼠骨髓中的淋巴谱系细胞在激素敏感的早期阶段与其他血细胞的细胞不同”Semin Nutrition.. 14. 385-394 (2002)

Takafumi Yokota, et al.: "Unique properties of fetal lymphoid progenitors identified according to RAG1 gene expression."Immunity. 19. 365-375 (2003)

Takafumi Yokota 等人：“根据 RAG1 基因表达鉴定胎儿淋巴祖细胞的独特特性。”免疫。

Takafumi Yokota, Taku Kouro, Jun Hirose, Hideya Igarashi, Karla P.Garrett, Sophia C.Gregory, Nobuo Sakaguchi, John J.T.Owen, Paul W.: "Kincade Unique properties of fetal lymphoid progenitors identified according to RAG1 gene expression."Immunity. 18. 365-

Takafumi Yokota、Taku Kouro、Jun Hirose、Hideya Igarashi、Karla P.Garrett、Sophia C.Gregory、Nobuo Sakaguchi、John J.T.Owen、Paul W.：“Kincade 根据 RAG1 基因表达鉴定了胎儿淋巴祖细胞的独特特性。”