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

点击翻译按钮获取中文摘要

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