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。 IL-6受体复合物由IL-6受体A链（IL-6Rα）和GP130组成，后者通常被IL-6细胞因子家族的成员用作信号传递分子。由IL-6受体复合物介导的特定细胞内信号，例如转录3（STAT3）的信号传感器和活化剂，细胞外信号调节激酶（ERK）1/2被认为是造成多种细胞反应的原因。 CD45抗原最初的特征是白细胞共同抗原，除成熟的红细胞和血小板外，在所有造血细胞上表达。通过CD45光晶酶对SRC家族激酶的COOH末端酪氨酸居住地的去磷酸化已实施了SRC家族激酶激活的机制。活化的SRC家族激酶在下游介导了几种细胞外刺激的信号……更多，例如生长因子，细胞因子和抗原刺激，从而导致初始信号的多样化和扩增。尽管CD45的作用已广泛研究B和T细胞中的抗原受体，但其在其他造血细胞中的物理后果在很大程度上仍然未知。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。这是MM似乎是一个很好的例子，可以在细胞因子促进的细胞增殖中解决CD45分子的生物学功能，IL-6。在MM中，IL-6仅增强了CD45^+肿瘤细胞的增殖，即尽管STAT3和ERK1/2可以激活CD45^+和CD45^ - 细胞中的IL-6，但SRC家族激酶的IL-6独立激活也可以激活IL-6。此外，IL-6诱导的CD45^+ U266骨髓瘤细胞的增殖被LYN特异性的反义寡脱氧核苷酸或选择性SRC激酶抑制剂显着抑制。这些结果表明，STAT和ERK1/2的激活不足以IL-6诱导的骨髓瘤细胞系的增殖，而骨髓瘤细胞系需要SRC家族激酶激活，而与IL-6刺激无关。这是，与CD45表达相关的SRC家族激酶的激活是IL-6骨髓瘤细胞系增殖的先决条件。我们提出了一种IL-6诱导的细胞增殖的机制，该机制严格取决于骨髓瘤中的细胞环境。这也得到了另一种发现，即表达成纤维细胞生长因子受体（FGFR）3的KMS11响应于IL-6与FGF一起响应IL-6。仅IL-6或FGF就无法增强KMS11骨髓瘤细胞系的增殖。 FGF可以激活与IL-6不同的几种与IL-6不同的信号分子，并且两者共同诱导不表达CD45的KMS11中的增殖信号。较少的