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Signal transduction of IL-6 in myeloma cells

IL-6在骨髓瘤细胞中的信号转导

基本信息

批准号：
09044301
负责人：
YOSHIZAKI Kazuyuki
金额：
$ 3.07万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044301/
关键词：
multiple myeloma IL-6 SSI-1 MAPK STAT1 STAT3 negative feedback STAT インターロイキン6

项目摘要

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.

白细胞介素-6（IL-6）是多发性骨髓瘤（MM）细胞的一种有效生长因子。它还可以预防皮质类固醇诱导的一些骨髓瘤细胞胞浆蛋白沉积和Fas抗原（CD 95）的交联。已经显示IL-6使用两种胞质内信号转导途径：（i）gpl30 * Ras * MARK * NF-IL 6。(ii)gp130 * JAK * STAT 3和/或STAT 1在本研究的第一年，我们的同事安德森博士阐明了前者途径用于生长刺激信号，我们还证明了STAT 3靶基因产物之一可以抑制STAT 3的磷酸化，并被指定为STAT诱导的STAT抑制剂-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种骨髓瘤细胞系中响应于IL-6刺激的表达和诱导。IL-6对STAT3酪氨酸磷酸化的抑制与SSI-1的组成性表达密切相关，而与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某些骨髓瘤细胞IL-6的JAK-STAT信号通路受损。SSI-1的人工组成型表达显著抑制OCI-My5细胞中的STAT3磷酸化，OCI-My5细胞代表其STAT3可被IL-6磷酸化的MM细胞。在IL-6不能磷酸化STAT3的MM细胞株ARH77中，反义SSI-1基因的导入使STAT3的酪氨酸磷酸化得以恢复。这些结果证实了SSI-1的组成型表达失调导致了某些MM细胞对IL-6的反应性缺失，其机制有待进一步研究。