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

基本信息

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

项目摘要

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

白介素6（IL-6）在不同细胞中具有多种生物学功能，是人骨髓瘤细胞的生长因子，由IL-6受体a链（IL-6Rα）和gp130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，例如信号转导子和转录激活子 3。 (STAT3) 和细胞外信号调节激酶 (ERK) 1/2 被认为负责诱导多种细胞反应，CD45 抗原最初被定性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。 CD45 磷酸酶对 src 家族激酶的 COOH 末端酪氨酸残基进行去磷酸化，这与 src 家族激酶激活的机制有关。激活的 src 家族激酶介导多种细胞外刺激信号的下游，例如生长因子、细胞因子和抗原刺激，导致初始信号的多样化和放大，尽管 CD45 在 B 抗原受体中的作用已被广泛研究。和 T 细胞，其在其他造血细胞中的生理后果仍然很大程度上未知，我们最近发现表达 CD45 的骨髓瘤细胞在多发性骨髓瘤 (MM) 中形成增殖群体，因此，MM 似乎是一个很好的例子。其中为了解决细胞因子 IL-6 促进的细胞增殖中 CD45 分子的生物学功能，在 MM 中，IL-6 仅增强具有不依赖于 IL-6 的 src 家族激活的 CD45^+ 肿瘤细胞的增殖。尽管在 CD45^+ 和 CD45^- 细胞中 STAT3 和 ERK1/2 可以响应 IL-6 而被激活，但 IL-6 诱导的 CD45^+ U266 增殖Lyn 特异性反义寡脱氧核苷酸或选择性 src 激酶抑制剂显着抑制骨髓瘤细胞。这些结果表明 STATS 和 ERK1/2 的激活不足以促进需要 src 家族激酶的 IL-6 诱导的骨髓瘤细胞系增殖。因此，与 CD45 表达相关的 src 家族激酶的激活是 IL-6 增殖的先决条件。 IL-6 诱导细胞增殖的机制严格依赖于骨髓瘤中的细胞环境。另一项发现也支持了这一点，即表达成纤维细胞生长因子受体 (FGFR) 3 的 KMS11 响应 IL-6 和 FGF 而增殖。单独的IL-6或FGF不能增强KMS11骨髓瘤细胞系的增殖，FGF可以激活与IL-6不同的几种信号分子，并且两者共同最终诱导KMS11中的增殖信号，从而增强KMS11骨髓瘤细胞系的增殖。不表达CD45。