Signal transduction of IL-6 in myeloma cells

白介素6(IL-6)被认为是多发性骨髓瘤(MM)细胞的一种强有力的生长因子。它还可以阻止某些骨髓瘤细胞由皮质类固醇诱导的细胞凋亡，以及Fas抗原(CD95)的交联。IL-6有两条胞浆内信号转导途径：(I)gpl30*RAS*Mark*NF-IL6。(Ii)gpl30*JAK*STAT3和/或STAT1在本研究的第一年，我们的同事Anderson博士阐明了前一条途径用于生长刺激信号。我们还证明了STAT3靶基因产物之一可以抑制STAT3的磷酸化，被命名为STATS诱导的STAT抑制物-1(SSI-1)。SSI-1可能是JAK-STAT信号通路的负反馈因子。为了阐明SSI-1及其家族分子在多发性骨髓瘤发病机制中的可能作用，我们检测了SSI-1及其家族分子在IL-6刺激下在6种骨髓瘤细胞系中的表达和诱导。IL-6诱导的STAT3酪氨酸磷酸化障碍与SSI-1的组成性表达密切相关，而与SSI-2、SSI-3、SSI-4或SSI-6的组成性表达无关，提示SSI-1的异常表达可能是某些骨髓瘤细胞IL-6 JAK-STAT信号受损的原因。在OCI-My5细胞中，SSI-1的人工组成型表达显著抑制了STAT3的磷酸化，代表了其STAT3可被LL-6磷酸化的MM细胞。相反，通过将反义SSI-1基因导入代表其STAT3不能被IL-6磷酸化的MM细胞的ARH77中，STAT3的酪氨酸酶磷酸化被恢复。这些数据证实了SSI-1的结构性表达失控导致了一些MM细胞对IL-6缺乏反应，这种转录失控的机制还有待进一步研究。

Interleukin-6(IL-6) is known to be a potent growth factor of multiple myeloma(MM) cells. It also prevents some myeloma cells fremapeptosis induced by corticosteroids, and crosslinking of Fas antigen (CD95). IL-6 has been shown to use two intracytoplasmic signal transducing pathways : (i) gpl3O * Ras * MARK * NF-IL6. (ii) gpl30 * JAK * STAT3 and/or STAT1 In the first year of this study, our collegue Dr.Anderson elucidated that the formrer pathway was used for growth stimulatory signal We also demonstrated that one of the STAT3-target gene products could inhibit the phosphorylatinn of STAT3 and was designated as STATs-induced STAT inhibitor-1 (SSI-1. The SSI-1 appears to act as a negative feedback factor of JAK-STAT signaling pathway. To elucidate a possible role in the pathogenesis of MM of SSI-1 and its family molecules which have a constructive homology with SSI-1, we have examined their expression and induction in six myeloma cell line in response to IL-6 stimulation. Close relation was found between disability in tyrosine-phosphorylation of STAT3 by IL-6 and constitutive expression of SSI-1 but not of SSI-2 SSI-3, SSI-4 or SSI-6, suggesting the abnormal expression of SSI-1 may cause the impaired JAK-STAT signaling of IL-6 in some myeloma cells. Artificial constitutive expression of SSI-1 markedly suppressed STAT3 phosphorylation in OCI-My5 cells which represent MM cells whose STAT3 could be phosphorylated by lL-6. On the contrary, tyrosime-phosphorylation of STAT3 was restored by introducing anti-sense SSI-1 gene in ARH77 which represent MM cells whose STAT3 could not be phosphorylated by IL-6.These data confirmed deregulated constitutive expression of SSI-1 caused the lack of response to IL-6 in some MM cell lines.Further study will be required to understand the mechanisms for such transcriptional deregulation of SSI-1.