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.

某些患者骨髓标本中淋巴样祖细胞缺乏症的模式表明，这些细胞可能受到抗炎疗法的影响。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通过暴露于糖皮质激素来抑制。用丁克萨米松处理的小鼠进行的研究表明，循环B谱系前体的选择性耗竭。相比之下，不保留了成熟的，非分裂的CD45R^<hi> CD19^<hi>淋巴细胞，髓样祖细胞和干细胞，具有移植时产生淋巴细胞的潜力。 lin^-il-7r^+ flk-2^+ pro-lymphocytes也下降了，但不如早期的lin^-c-kit^<hi> sca-1^<hi>骨骨髓的tdt^+细胞迅速。使用人M转基因小鼠和RAG1/GFP敲击动物，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的其他特性的激素敏感细胞。此外，与骨髓和脾脏中成熟的淋巴细胞相比，具有RAG1表达最近史的细胞更具有糖皮质激素敏感性。保护携带人Bcl-2转基因的小鼠中的淋巴细胞祖细胞受到对地塞米松治疗的保护。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。在肾上腺切除或RU486治疗的小鼠的骨髓中发现B谱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管的稳态调节。这些发现是关于控制中央淋巴机构中淋巴细胞产生的手段的信息，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。”