Cancer Cell Biology Program, West Virginia University, Morgantown, WV 26506, USA.
Cytokine. 2012 May;58(2):245-52. doi: 10.1016/j.cyto.2012.01.012. Epub 2012 Feb 21.
Bone marrow stromal cells (BMSC) and osteoblasts are critical components of the microenvironment that support hematopoietic recovery following bone marrow transplantation. Aggressive chemotherapy not only affects tumor cells, but also influences additional structural and functional components of the microenvironment. Successful reconstitution of hematopoiesis following stem cell or bone marrow transplantation after aggressive chemotherapy is dependent upon components of the microenvironment maintaining their supportive function. This includes secretion of soluble factors and expression of cellular adhesion molecules that impact on development of hematopoietic cells. In the current study, we investigated the effects of chemotherapy treatment on BMSC and human osteoblast (HOB) expression of interleukin-6 (IL-6) as one regulatory factor. IL-6 is a pleiotropic cytokine which has diverse effects on hematopoietic cell development. In the current study we demonstrate that exposure of BMSC or HOB to melphalan leads to decreases in IL-6 protein expression. Decreased IL-6 protein is the most pronounced following melphalan exposure compared to several other chemotherapeutic agents tested. We also observed that melphalan decreased IL-6 mRNA in both BMSC and HOB. Finally, using a model of BMSC or HOB co-cultured with myeloma cells exposed to melphalan, we observed that IL-6 protein was also decreased, consistent with treatment of adherent cells alone. Collectively, these observations are of dual significance. First, suggesting that chemotherapy induced IL-6 deficits in the bone marrow occur which may result in defective hematopoietic support of early progenitor cells. In contrast, the decrease in IL-6 protein may be a beneficial mechanism by which melphalan acts as a valuable therapeutic agent for treatment of multiple myeloma, where IL-6 present in the bone marrow acts as a proliferative factor and contributes to disease progression. Taken together, these data emphasize the responsiveness of the microenvironment to diverse stress that is important to consider in therapeutic settings.
骨髓基质细胞（BMSC）和成骨细胞是支持骨髓移植后造血恢复的微环境的关键组成部分。强烈的化疗不仅会影响肿瘤细胞，还会影响微环境的其他结构和功能成分。在强烈的化疗后进行干细胞或骨髓移植后，造血的成功重建取决于微环境的组成部分维持其支持功能。这包括分泌可溶性因子和表达细胞粘附分子，这些因素影响造血细胞的发育。在目前的研究中，我们研究了化疗治疗对骨髓基质细胞和人成骨细胞（HOB）白细胞介素 6（IL-6）表达的影响，IL-6 是一种调节因子。IL-6 是一种多效细胞因子，对造血细胞的发育有多种影响。在目前的研究中，我们证明暴露于美法仑会导致 BMSC 或 HOB 中 IL-6 蛋白表达减少。与测试的几种其他化疗药物相比，美法仑暴露后 IL-6 蛋白减少最为明显。我们还观察到美法仑降低了 BMSC 和 HOB 中的 IL-6 mRNA。最后，使用骨髓基质细胞或成骨细胞与暴露于美法仑的骨髓瘤细胞共培养的模型，我们观察到 IL-6 蛋白也减少了，这与单独处理贴壁细胞一致。总的来说，这些观察结果具有双重意义。首先，这表明骨髓中发生了化疗诱导的 IL-6 缺陷，这可能导致早期祖细胞的造血支持缺陷。相比之下，IL-6 蛋白的减少可能是美法仑作为治疗多发性骨髓瘤的有价值治疗剂的有益机制，骨髓中存在的 IL-6 作为增殖因子并促进疾病进展。总之，这些数据强调了微环境对各种应激的反应性，这在治疗环境中是很重要的。
