多发性骨髓瘤血管内皮生长因子和白细胞介素-6相互作用的研究  

The interaction of vascular endothelial growth factor and interleukin-6 in multiple myeloma

作　　者：张蕾[1] 陈世伦[1] 陈文明[1] 刘晋伟[1] 

机构地区：[1]首都医科大学附属北京朝阳医院血液科,100020

出　　处：《中华内科杂志》2005年第2期85-88,共4页Chinese Journal of Internal Medicine

摘　　要：目的研究人类多发性骨髓瘤(MM)细胞系和MM患者骨髓基质细胞(BMSCs)之间相互作用对血管内皮生长因子(VEGF)和IL-6分泌的调控作用,分析VEGF和IL-6的相互作用在MM发病机制中的意义.方法建立MM-BMSCs和正常人-BMSCs(N-BMSCs)的培养体系,用IL-6、抗 IL-6抗体、VEGF、抗VEGF抗体作用于BMSCs和(或)MM细胞系U266后,ELISA方法检测其VEGF和 IL-6的分泌量.结果 U266分泌VEGF,但不分泌IL-6,而MM-BMSCs和N-BMSCs既分泌VEGF又分泌IL-6.重组人VEGF刺激BMSCs后,以时间和剂量依赖性的方式诱导IL-6的分泌,此效应可被抗VEGF抗体抑制.外源性IL-6促进BMSCs分泌VEGF.当U266与BMSCs黏附后,VEGF 分泌增加2.5～5.0倍,IL-6增加5.5～9.0倍,两者差异有统计学意义(P<0.05);分别加入抗VEGF或抗IL-6抗体,IL-6或VEGF的分泌受抑.重组人IL-6作用于U266,可诱导剂量依赖性的VEGF分泌的增加,此反应可被抗IL-6抗体抑制.结论在MM中,MM细胞和BMSCs之间的相互作用调节VEGF和 IL-6的分泌,促进MM细胞的生长和血管新生,在MM的发病机制中发挥重要作用,为针对骨髓微环境的靶位治疗提供了理论依据.Objective 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. Methods 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.Results 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 presencet of a monoclonal antihuman IL-6 antibody.Conclusions 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.

关 键 词：多发性骨髓瘤 相互作用 白细胞介素-6 血管内皮生长因子(VEGF) 抗IL-6抗体 抗VEGF抗体 BMSCs ELISA方法 剂量依赖性 骨髓基质细胞 发病机制 人IL-6 骨髓微环境 调控作用 培养体系 分泌增加 血管新生 靶位治疗 细胞系 M细胞 

分 类 号：R733.3[医药卫生—肿瘤] R541.4[医药卫生—临床医学]