SHIP1 Inhibition Increases Immunoregulatory Capacity and Triggers Apoptosis of Hematopoietic Cancer Cells
SHIP1 Inhibition Increases Immunoregulatory Capacity and Triggers Apoptosis of Hematopoietic Cancer Cells
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DOI：
10.4049/jimmunol.0902844
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Kerr, William G.
中科院分区：
文献类型：
--
作者：
Brooks, Robert;Fuhler, Gwenny M.;Kerr, William G.
遗传学研究表明，SHIP1限制了体内血细胞的产生和免疫调节细胞的数量。我们推测，SHIP1的分子靶向可能增加血细胞的产生和增强免疫调节能力。在这项研究中，我们报告了SHIP1，3α-氨基胆烷(3AC)的一种化学抑制剂的鉴定。3AC治疗显著扩大了髓系免疫调节细胞隔间，并削弱了外周淋巴组织启动同种异体T细胞反应的能力。此外，3AC治疗大大增加了粒细胞的产生，而不会引发SHIP1(-/-)小鼠中观察到的髓系相关肺实变。此外，3AC还能促进骨髓抑制宿主的红细胞、中性粒细胞和血小板的恢复。有趣的是，我们还发现化学抑制Shin会触发血液癌细胞的凋亡。因此，Shin抑制剂代表了一类新的小分子，具有促进同种异体移植、促进血细胞生成和改善恶性血液病治疗的潜力。免疫学杂志，2010,184：3582-3589。
Genetic studies revealed that SHIP1 limits blood cell production and immune regulatory cell numbers in vivo. We postulated that molecular targeting of SHIP1 might enhance blood cell production and increase immunoregulatory capacity. In this study, we report the identification of a chemical inhibitor of SHIP1, 3 alpha-aminocholestane (3AC). Treatment with 3AC significantly expands the myeloid immunoregulatory cell compartment and impairs the ability of peripheral lymphoid tissues to prime allogeneic T cell responses. In addition, 3AC treatment profoundly increases granulocyte production without triggering the myeloid-associated lung consolidation observed in SHIP1(-/-) mice. Moreover, 3AC also enhances RBC, neutrophil, and platelet recovery in myelosuppressed hosts. Intriguingly, we also find that chemical inhibition of SHIN triggers apoptosis of blood cancer cells. Thus, SHIN inhibitors represent a novel class of small molecules that have the potential to enhance allogeneic transplantation, boost blood cell production, and improve the treatment of hematologic malignancies. The Journal of Immunology, 2010, 184: 3582-3589.