Synergistic inhibition in vivo of bone marrow myeloid progenitors by myelosuppressive chemokines and chemokine-accelerated recovery of progenitors after treatment of mice with Ara-C
Synergistic inhibition in vivo of bone marrow myeloid progenitors by myelosuppressive chemokines and chemokine-accelerated recovery of progenitors after treatment of mice with Ara-C
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DOI：
10.1016/j.exphem.2006.04.007
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发表时间：
2006-08-01
影响因子：
2.6
通讯作者：
Hromas, Robert
中科院分区：
文献类型：
--
作者：
Broxmeyer, Hal E.;Pelus, Louis M.;Hromas, Robert
Objective.选择的趋化因子在体外抑制造血祖细胞（HPC）的增殖;其中一些已经证明在体内抑制骨髓生成。由于骨髓抑制趋化因子在体外与其他骨髓抑制趋化因子协同作用，我们试图确定是否额外的趋化因子在体外活性的骨髓抑制在体内和骨髓抑制趋化因子的组合是否协同作用，在体内抑制骨髓生成。我们还评估了三种趋化因子在体内对阿糖胞苷诱导的HPC减少的骨髓保护作用。C3 H/HeJ小鼠用于分析趋化因子的体内影响，终点是对HPC的绝对数量和循环状态的影响。当与CCL 2、CCL 3、CCL 19、CCL 20、CXCL 4、CXCL 5、CXCL 8、CXCL 9和XCL 1沿着使用时，体内HPC的绝对数量和循环状态均出现剂量依赖性显著降低。以下两种趋化因子的组合导致体内骨髓抑制，其浓度远低于每种趋化因子单独诱导的浓度：CCL 3加XCL 8或CXCL 4、CXCL 8加CXCL 4、CCL 2加CCL 20或CXCL 9、CCL 20加CXCL 9、CXCL 5加XCL 1或CCL 19、XCL 1加CCL 19和CCL 3加CCL 19。此外，注射CXCL 8、CXCL 4或嵌合CXCL 8/CXCL 4蛋白CXCL 8 M1的小鼠表现出响应Ara-C给药毒性作用的HPC绝对数量的加速恢复。以前显示的许多趋化因子在体外表现出对HPC增殖的抑制作用，现在证明在体内也诱导骨髓抑制。此外，低剂量的两种骨髓抑制性趋化因子的组合在一起施用时显示出体内协同抑制。此外，趋化因子，包括CXCL 8 M1嵌合蛋白，先前显示在体外和体内表现出增强的HPC增殖抑制，在用Ara-C治疗小鼠后加速HPC恢复。这些结果可能是用于未来的临床效用的趋化因子在骨髓抑制/骨髓保护设置。(c)2006年国际实验血液学学会。爱思唯尔公司出版
Objective. Selected chemokines suppress proliferation of hematopoietic progenitor cells (HPCs) in vitro; some of these have demonstrated inhibition of myelopoiesis in vivo. Because myelosuppressive chemokines synergize in vitro with other myelosuppressive chemokines, we sought to determine whether additional chemokines active in vitro were myelosuppressive in vivo and whether combinations of myelosuppressive chemokines synergized in vivo to dampen myelopoiesis. We also evaluated three chemokines in vivo for myeloprotection against Ara-C-induced decreases in HPCs.Methods. C3H/HeJ mice were used for analysis of in vivo influence of chemokines, with the end points being effects on absolute numbers and cycling status of HPCs.Results. When used along, CCL2, CCL3, CCL19, CCL20, CXCL4, CXCL5, CXCL8, CXCL9, and XCL1 caused do e-dependent significant decreases in absolute numbers and cycling status of HPCs in vivo. The following combinations of two chemokines resulted in in vivo myelosuppression at concentrations much lower than that induced by each chemokine alone: CCL3 plus either XCL8 or CXCL4, CXCL8 plus CXCL4, CCL2 plus either CCL20 or CXCL9, CCL20 plus CXCL9, CXCL5 plus either XCL1 or CCL19, XCL1 plus CCL19, and CCL3 plus CCL19. Also, mice injected with CXCL8, CXCL4, or the chimeric CXCL8/ CXCL4 protein CXCL8M1 manifested accelerated recovery of absolute numbers of HPCs in response to the toxic effects of Ara-C administration.Conclusions. A number of chemokines shown previously to manifest inhibitory effects in vitro for proliferation of HPCs are now demonstrated to also induce myelosuppression in vivo. Moreover, combinations of low dosages of two myelosuppressive chemokines when administered together demonstrate synergistic suppression in vivo. Additionally, chemokines, including a CXCL8M1 chimeric protein previously shown to manifest enhanced suppression of HPC proliferation in vitro and in vivo, accelerate HPC recovery after treatment of mice with Ara-C. These results may be of use for future clinical utility of chemokines in a myelosuppressive/myeloprotective setting. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc.