Signal transduction of IL-6 in myeloma cells

白细胞介素-6（IL-6）被认为是多发性骨髓瘤（MM）细胞的一种有效的生长因子。它还可以防止一些骨髓瘤细胞由皮质类固醇和Fas抗原（CD95）交联诱导的自由凋亡。IL-6已被证明使用两种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Dr.Anderson阐明了前者通路用于生长刺激信号，我们也证明了STAT3的一个靶基因产物可以抑制STAT3的磷酸化蛋白，并被命名为STATs-induced STAT inhibitor-1 （SSI-1）。SSI-1似乎是JAK-STAT信号通路的负反馈因子。为了阐明SSI-1及其与SSI-1具有构建同源性的家族分子在MM发病机制中的可能作用，我们研究了它们在6株骨髓瘤细胞系中对IL-6刺激的表达和诱导。发现IL-6酪氨酸磷酸化STAT3的失能与SSI-1的组成性表达密切相关，而SSI-2、SSI-3、SSI-4和SSI-6的组成性表达无关，提示SSI-1的异常表达可能导致部分骨髓瘤细胞中IL-6的JAK-STAT信号通路受损。在OCI-My5细胞中，si -1的人工组成性表达显著抑制STAT3的磷酸化，OCI-My5细胞代表STAT3可被lL-6磷酸化的MM细胞。相反，通过在ARH77中引入反义SSI-1基因，STAT3的酪氨酸磷酸化得以恢复，ARH77代表了STAT3不能被IL-6磷酸化的MM细胞。这些数据证实，在一些MM细胞系中，SSI-1的非调控构成性表达导致对IL-6缺乏反应。需要进一步的研究来了解SSI-1转录解除管制的机制。

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.