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

白介素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受体复合体由IL-6受体a链(IL-6Rα)和gp130组成，后者是IL-6细胞因子家族成员常用的信号转导分子。由IL-6受体复合体介导的特异性细胞内信号转导和转录激活因子3(STAT3)和细胞外信号调节激酶(ERK)1/2被认为是诱导多种细胞反应的重要因素。CD45抗原最初的特征是除成熟的红细胞和血小板外，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COOH末端酪氨酸残基的去磷酸化被认为是src家族激酶激活的一种机制。激活的src家族激酶介导了几种细胞外刺激…信号的下游。更多，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。虽然CD45在B和T细胞中的抗原受体中的作用已经被广泛研究，但它在其他造血细胞中的生理影响仍然很大程度上是未知的。我们最近发现，在多发性骨髓瘤(MM)中，表达CD45的骨髓瘤细胞形成了一个增殖群。因此，MM似乎是一个很好的例子，可以解决CD45分子在细胞因子IL-6促进的细胞增殖中的生物学功能。在MM中，尽管CD45^+和CD45^-细胞中的STAT3和ERK1/2可以被IL-6激活，但IL-6只促进CD45^+肿瘤细胞的增殖，而CD45^+肿瘤细胞具有IL-6依赖的src家族激酶的激活。此外，IL-6诱导的CD45~+U266骨髓瘤细胞的增殖可被Lyn特异性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，对于IL-6诱导的骨髓瘤细胞株的增殖，STATS和ERK1/2的激活不足以满足需要src家族激酶激活而不依赖IL-6刺激的骨髓瘤细胞株的增殖。因此，与CD45表达相关的src家族激酶的激活是IL-6促进骨髓瘤细胞系增殖的先决条件。我们提出了一种IL-6诱导细胞增殖的机制，该机制严格依赖于骨髓瘤的细胞环境。另一项发现也支持这一发现，即表达成纤维细胞生长因子受体(FGFR)3的KMS11在IL-6和成纤维细胞生长因子共同作用下增殖。单独使用IL-6或成纤维细胞生长因子不能促进KMS11骨髓瘤细胞系的增殖。成纤维细胞生长因子可以激活一些不同于IL-6的信号分子，最终共同诱导不表达CD45的KMS11细胞的增殖信号。较少

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