Functional analysis of the molecules modulating the proliferative signals of human myeloma cells by IL-6

IL-6调节人骨髓瘤细胞增殖信号分子的功能分析

• 批准号: 12670991
• 负责人: ISHIKAWA Hideaki
• 金额: $ 2.11万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670991/
• 关键词: multiple myeloma; IL-6; cell proliferation; CD45; FGFR3; src family kinase; STAT3; ERK1; 2; 骨髄腫; PLC; Caイオン; CD19; src; STAT; MAPK; アポトーシス

Interleukin-6 (IL-6) has a variety of biological functions in different cells and is a growth factor for human myeloma cells. IL-6 receptor complexes consist of the IL-6 receptor a chain (IL-6Rα) and gp130, the latter being commonly used as a signal-transducing molecule by the members of the IL-6 family of cytokines. Specific intracellular signals mediated by IL-6 receptor complexes, such as signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) 1/2, are considered to be responsible for inducing a variety of cellular responses. CD45 antigens are initially characterized as leukocyte common antigen expressed on all hematopoietic cells except for mature erythrocytes and platelets. Dephosphorylation of the COOH-terminal tyrosine residue of src family kinases by CD45 phosphatase has been implicated a mechanism of src family kinase activation. The activated src family kinases mediate downstream the signals of several extracellular stimuli … More , such as growth factors, cytokines, and antigen stimulation, leading to diversification and amplification of the initial signals. Although the roles of CD45 have been extensively studied for antigen receptors in B and T cells, its physiological consequences in other hematopoietic cells remain largely unknown. We recently found that myeloma cells expressing CD45 form a proliferating population in multiple myeloma (MM). Thus, MM seems a good example in which to address the biological functions of CD45 molecules in cell proliferation promoted by the cytokine, IL-6. In MM, IL-6 only enhanced the proliferation of CD45^+ tumor cells that harbored the IL-6-independent activation of src family kinases even though STAT3 and ERK1/2 could be activated in response to IL-6 in both CD45^+ and CD45^- cells. Furthermore, the IL-6-induced proliferation of CD45^+ U266 myeloma cells was significantly suppressed by Lyn-specific antisense oligodeoxynucleotides or a selective src kinase inhibitor. These results indicates that the activation of both STATS and ERK1/2 is not sufficient for IL-6-induced proliferation of myeloma cell lines that require src family kinase activation independent of IL-6 stimulation. Thus, the activation of the src family kinases associated with CD45 expression is a prerequisite for the proliferation of myeloma cell lines by IL-6. We propose a mechanism for IL-6-induced cell proliferation that is strictly dependent upon the cellular context in myeloma.This is also supported by another finding that KMS11 expressing fibroblast growth factor receptor (FGFR) 3 proliferated in response to IL-6 together with FGF. IL-6 or FGF alone failed to enhance the proliferation of KMS11 myeloma cell line. FGF could activated several signaling molecules different from those by IL-6, and both together finally induce the proliferative signals in KMS11 that does not express CD45. Less

白细胞介素-6（IL-6）在不同的细胞中具有多种生物学功能，是人骨髓瘤细胞的生长因子。IL-6受体复合物由IL-6受体α链（IL-6 R α）和gp 130组成，后者通常被IL-6细胞因子家族成员用作信号转导分子。由IL-6受体复合物介导的特异性细胞内信号，如信号转导子和转录激活子3（STAT 3）和细胞外信号调节激酶（ERK）1/2，被认为是诱导多种细胞应答的原因。CD 45抗原最初被表征为在除成熟红细胞和血小板之外的所有造血细胞上表达的白细胞共同抗原。src家族激酶的羧基端酪氨酸残基被CD 45磷酸酶去磷酸化是src家族激酶激活的一种机制。活化的src家族激酶介导下游的几种细胞外刺激的信号 ...更多信息 如生长因子、细胞因子和抗原刺激，导致初始信号的多样化和扩增。尽管CD 45在B和T细胞中抗原受体的作用已被广泛研究，但其在其他造血细胞中的生理后果在很大程度上仍然未知。我们最近发现，在多发性骨髓瘤（MM）中，表达CD 45的骨髓瘤细胞形成增殖群体。因此，MM似乎是一个很好的例子，其中解决了CD 45分子在细胞因子IL-6促进的细胞增殖中的生物学功能。在多发性骨髓瘤中，IL-6仅促进了具有非IL-6依赖性src家族激酶激活的CD 45 ^+肿瘤细胞的增殖，尽管在CD 45 ^+和CD 45 ^-细胞中，STAT 3和ERK 1/2都可以被IL-6激活。此外，IL-6诱导的CD 45 ^+ U266骨髓瘤细胞的增殖被Lyn-specific反义寡核苷酸或选择性src激酶抑制剂显著抑制。这些结果表明，STATS和ERK 1/2的激活对于需要src家族激酶激活而不依赖于IL-6刺激的骨髓瘤细胞系的IL-6诱导的增殖是不够的。因此，与CD 45表达相关的src家族激酶的活化是IL-6使骨髓瘤细胞系增殖的先决条件。我们提出IL-6诱导细胞增殖的机制是严格依赖于骨髓瘤的细胞环境，这也得到了另一个发现的支持，即表达成纤维细胞生长因子受体（FGFR）3的KMS 11在IL-6和FGF的共同作用下增殖。单独应用IL-6或FGF不能促进KMS-11细胞的增殖。FGF可激活多种与IL-6不同的信号分子，二者共同诱导不表达CD 45的KMS 11细胞产生增殖信号。少

项目成果

Ishikawa, H.: "CD19 expression and growth inhibition of tumors in human multiple myeloma"Leuk. Lymphoma. (in press). (2002)

Ishikawa, H.：“人多发性骨髓瘤中 CD19 的表达和肿瘤生长抑制”Leuk。

Ishikawa, H.: "CD19 expression and growth inhibition of tumors in human multiple myeloma."Leuk. Lymphoma. (in press). (2002)

Ishikawa, H.：“人类多发性骨髓瘤中的 CD19 表达和肿瘤生长抑制。”Leuk。

Ishikawa,H.: "Pax-5 genes and CD19 molecules in human myeloma"Jpn. J. Clin. Hematol. 41 (5). 404-407 (2000)

Ishikawa,H.：“人类骨髓瘤中的 Pax-5 基因和 CD19 分子”Jpn。

Ishikawa,H.: "Pax-5 and plasmacytoid lymphoma"Hematol, Frontier. 10 (9). 1185-1192 (2000)

Ishikawa,H.：“Pax-5 和浆细胞样淋巴瘤”Hematol，Frontier。

Ishikawa,H.: "Growth mechanisms of myeloma cells -mechanism of proliferation by interleukin-6"Hematol, Frontier. 12 (5) (in press). (2002)

Ishikawa,H.：“骨髓瘤细胞的生长机制 - 白细胞介素 6 的增殖机制”Hematol，Frontier。