MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells
MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells
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DOI：
10.1016/j.exphem.2004.11.015
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发表时间：
2005-03-01
影响因子：
2.6
通讯作者：
Roodman, GD
中科院分区：
文献类型：
--
作者：
Oba, Y;Lee, JW;Roodman, GD
目标。巨噬细胞炎症蛋白-let(MIP-1α)是一种由原代多发性骨髓瘤(MM)细胞产生的破骨细胞(OCL)刺激因子，可增加MM小鼠模型的骨破坏和肿瘤负担。几种趋化因子受体(CCR1、CCR5和CCR9)介导了MIP-1α的作用。在这项研究中，我们确定了这些因素中的哪一个介导了MIP-1α对人OCL形成和骨髓瘤细胞的影响。我们使用RT-PCR分析、CCR1和CCR5的中和抗体以及CCR1特异性拮抗剂和OCL形成实验来鉴定参与MIP-1α对骨髓瘤细胞的作用和OCL形成的MIP-1α受体。RT-PCR分析表明，CCR1和CCR5在高纯度的人OCL前体细胞、骨髓瘤细胞系和MM患者纯化的骨髓浆细胞中均有表达。抗CCR1或CCR5的中和抗体可抑制MIP-1α诱导的OCL形成。此外，单核细胞趋化蛋白-3(MCP-3)可显著抑制MIP-1α刺激的OCL的形成，而单核细胞趋化蛋白-3(MCP-3)与CCR1而不是CCR5结合，以及CCR1特异性拮抗剂BX471能显著抑制MIP-1α刺激的OCL形成。抗CCR1、抗CCR5或BX471还可抑制MIP-1α诱导的骨髓瘤细胞01整合素基因表达上调，抑制骨髓瘤细胞与基质细胞的黏附，抑制骨髓瘤细胞分泌IL-6。这些数据表明，MIP-1α利用CCR1或CCR5对OCL的形成和骨髓瘤细胞产生影响，而阻断CCR1或CCR5可以抑制OCL的形成和骨髓瘤细胞与基质细胞的黏附。(C)2005年国际实验血液学学会。由爱思唯尔公司出版。
Objectives. Macrophage inflammatory protein-let (MIP-1 alpha), an osteoclast (OCL) stimulatory factor produced by primary multiple myeloma (MM) cells, increases bone destruction and tumor burden in murine models of MM. Several chemokine receptors (CCR1, CCR5, and CCR9) mediate the effects of MIP-1 alpha. In this study, we determined which of these mediates the effects of MIP-1 alpha on human OCL formation and myeloma cells.Methods. We employed RT-PCR analysis, neutralizing antibodies to CCR1 and CCR5 as well as a CCR1-specific antagonist and OCL formation assays to identify the MIP-1 alpha receptors involved in MIP-1 alpha's effects on myeloma cells and OCL formation.Results. RT-PCR analysis demonstrated that both CCR1 and CCR5 were expressed by highly purified human OCL precursors, myeloma cell lines, and purified marrow plasma cells from MM patients. Neutralizing antibodies to CCR1 or CCR5 inhibited MIP-1 alpha-induced OCL formation. Furthermore, monocyte chemotactic protein-3 (MCP-3), which binds CCR1 but not CCR5 and the CCR1-specific antagonist, BX471, markedly inhibited OCL formation stimulated with MIP-1 alpha. Anti-CCR1, anti-CCR5, or BX471 also inhibited the upregulation of 01 integrin mRNA in myeloma cells induced by MIP-1 alpha, as well as the adherence of myeloma cells to stromal cells and IL-6 production by stromal cells in response to myeloma cells.Conclusion. These data demonstrate that MIP-1 alpha utilizes either CCR1 or CCR5 for its effects on OCL formation and myeloma cells, and that blocking either CCR1 or CCR5 inhibits OCL formation and myeloma cell adhesion to stromal cells. (c) 2005 International Society for Experimental Hematology. Published by Elsevier Inc.