Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis
Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis
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DOI：
10.1182/blood.v97.2.483
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发表时间：
2001-01-15
期刊：
影响因子：
20.3
通讯作者：
Dammacco, F
中科院分区：
文献类型：
--
作者：
Frassanito, MA;Cusmai, A;Dammacco, F
本研究采用流式细胞术对47例不同临床分期的多发性骨髓瘤（MM）患者和15例意义不明的单克隆γ病患者骨髓单核细胞产生的白细胞介素-6 （IL-6）进行了检测。在多发性骨髓瘤患者中，自分泌IL-6的产生与临床疾病分期平行，在耐药复发或原发性难愈性疾病患者中检测到syndecan-1(+)/IL-6（+）细胞的比例最大，表明肿瘤进展涉及产生IL-6的骨髓瘤细胞的扩增。作者评估了6个骨髓瘤细胞克隆（mcs）和2个骨髓瘤细胞系（IM-9和u - 166 -1970）骨髓瘤细胞的自分泌IL-6的产生、体外增殖和凋亡。在侵袭性疾病患者和IM-9细胞系中克隆的不依赖IL-6的MCC-2、MCC-3和MCC-5中观察到自分泌的IL-6产生。相反，依赖IL-6的MCC-1、MCC-4和MCC-B是syndecan-1（+）和IL-6（-）。克隆AH65的抗IL-6单克隆抗体结合IL-6- il - 6r α复合物，阻断IL-6(+) mcc的细胞增殖，碘化丙烯染色后流式细胞术评价显示mcc对细胞死亡的不同敏感性。产生IL-6的mcc表现出最小的自发凋亡和地塞米松诱导的凋亡，而IL-6(-) mcc则出现了规律的凋亡幅度。这些数据提供了自分泌IL-6反映骨髓瘤细胞高度恶性表型的证据。事实上，自分泌IL-6的产生和不受调控的凋亡可能诱导选择性IL-6（+）骨髓瘤细胞扩增，抵抗自发和药物诱导的细胞死亡。(C) 2001年由美国血液学会出版。
In this study, flow cytometry was used to evaluate interleukin-6 (IL-6) production by bone marrow mononuclear cells from 47 patients with multiple myeloma (MM) in different clinical stages and 15 patients with monoclonal gammopathy of undetermined significance. In patients with MM, autocrine IL-6 production paralleled the clinical disease stage, The largest proportion of syndecan-1(+)/IL-6(+) cells was detected in patients with resistant relapse or primary refractory disease, suggesting that tumor progression involves expansion of myeloma cells producing IL-6, The authors assessed autocrine IL-6 production and in vitro proliferation and apoptosis of myeloma cells in 6 myeloma cell clones (MCCs) and in 2 myeloma cell lines, namely IM-9 and U-266-1970, which showed different sensitivities to the addition of exogenous IL-6, Autocrine IL-6 production was observed in IL-6-independent MCC-2, MCC-3, and MCC-5 cloned from patients with aggressive disease and in the IM-9 cell line. In contrast, IL-6-dependent MCC-1, MCC-4, and MCC-B were syndecan-1(+) and IL-6(-). Blocking experiments with anti-IL-6 monoclonal antibody from clone AH65, which binds IL-6-IL-6R alpha complexes, prevented cell proliferation of IL-6(+) MCCs, Flow cytometry evaluations after propidium iodide staining revealed different susceptibilities of MCCs to cell death. IL-6-producing MCCs showed minimal spontaneous and dexamethasone-induced apoptosis, whereas a regular amplitude of apoptosis occurred in the IL-6(-) MCCs, These data provide evidence that autocrine IL-6 reflects a highly malignant phenotype of myeloma cells. In fact, autocrine IL-6 production and deregulated apoptosis may induce expansion of selective IL-6(+) myeloma cells resistant to spontaneous and drug-induced cell death. (C) 2001 by The American Society of Hematology.