Zhang Lei, Chen Shi-lun, Chen Wen-ming, Liu Jin-wei
Department of Hematology, Beijing Chaoyang Hospital, Capital University of Medical Sciences, Beijing 100020, China.
Zhonghua Nei Ke Za Zhi. 2005 Feb;44(2):85-8.
To study the interaction between human multiple myeloma (MM) cell line and MM-bone marrow stromal cells (BMSCs) modulated by mutual stimulation of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), and to analyze the role of VEGF and IL-6 in the pathogenesis of MM.
MM patient (MM-BMSCs) and normal donor-BMSCs (N-BMSCs) were established from the MNCs of MM and normal bone marrow. ELISA was performed to detect the expression of VEGF and IL-6 in culture supernatants of human MM cell lines U266, MM-BMSCs, N-BMSCs, and co-cultures of U266 and BMSCs in vitro. VEGF and IL-6 were detected in culture supernatants with or without IL-6, anti-IL-6, VEGF, anti-VEGF antibody.
Human MM cell line U266 secreted VEGF, but did not secrete IL-6. BMSCs from MM patients and normal donors secreted both VEGF and IL-6. BMSCs stimulated with recombinant human VEGF induced a time and dose-dependent increase in IL-6 secretion. The effects of VEGF were canceled by monoclonal anti-VEGF antibody. Exogenous IL-6 stimulated VEGF secretion of BMSCs. Importantly, when U266 cell were adhered to BMSCs, there was significant increase of VEGF (2.5 - 5.0 fold, P < 0.05) and IL-6 (5.5 - 9.0 fold, P < 0.05) secretion. The secretion of VEGF or IL-6 in BMSCs alone or co-cultures of BMSCs with U266 were inhibited by anti-human IL-6 or anti-human VEGF antibody. U266 cell stimulated with recombinant human IL-6 induced a dose-dependent increase in VEGF secretion, which was inhibited in the presence of a monoclonal antihuman IL-6 antibody.
The interaction between myeloma cells and marrow stromal cells modulates the secretion of VEGF and IL-6, facilitates myeloma cells growth and angiogenesis in MM. It plays an important role in the pathogenesis of MM. This study provides a theoretic basis for target therapy in the treatment of bone marrow microenvironment.
研究血管内皮生长因子（VEGF）和白细胞介素 - 6（IL - 6）相互刺激调节下人多发性骨髓瘤（MM）细胞系与MM骨髓基质细胞（BMSCs）之间的相互作用，并分析VEGF和IL - 6在MM发病机制中的作用。
从MM患者和正常供体的骨髓单个核细胞（MNCs）中建立MM患者BMSCs（MM - BMSCs）和正常供体BMSCs（N - BMSCs）。采用酶联免疫吸附测定（ELISA）法检测人MM细胞系U266、MM - BMSCs、N - BMSCs以及U266与BMSCs体外共培养上清液中VEGF和IL - 6的表达。在有或无IL - 6、抗IL - 6、VEGF、抗VEGF抗体的情况下，检测培养上清液中的VEGF和IL - 6。
人MM细胞系U266分泌VEGF，但不分泌IL - 6。MM患者和正常供体的BMSCs均分泌VEGF和IL - 6。重组人VEGF刺激BMSCs可诱导IL - 6分泌呈时间和剂量依赖性增加。VEGF的作用可被单克隆抗VEGF抗体抵消。外源性IL - 6刺激BMSCs分泌VEGF。重要的是，当U266细胞黏附于BMSCs时，VEGF（2.5 - 5.0倍，P < 0.05）和IL - 6（5.5 - 9.0倍，P < 0.05）分泌显著增加。单独的BMSCs或BMSCs与U266共培养时，VEGF或IL - 6的分泌均被抗人IL - 6或抗人VEGF抗体抑制。重组人IL - 6刺激U266细胞可诱导VEGF分泌呈剂量依赖性增加，在单克隆抗人IL - 6抗体存在时受到抑制。
骨髓瘤细胞与骨髓基质细胞之间的相互作用调节VEGF和IL - 6的分泌，促进MM中骨髓瘤细胞的生长和血管生成。它在MM发病机制中起重要作用。本研究为骨髓微环境治疗中的靶向治疗提供了理论依据。
