Usui Eiji, Nishii Kazuhiro, Katayama Naoyuki, Lorenzo V Felipe, Chen Fawen, Monma Fumihiko, Otsuki Takemi, Shiku Hiroshi
Second Department of Internal Medicine, Mie University School of Medicine, Mie, Japan.
Hematol J. 2004;5(6):505-12. doi: 10.1038/sj.thj.6200565.
Interferon-alpha (IFN-alpha) is used as a treatment for multiple myeloma, although its clinical effects remain controversial. Here, we investigated whether IFN-alpha altered the autocrine production of interleukin-6 (IL-6) or IL-10, both identified as key cytokines regulating myeloma cell growth/survival, and found that IL-6, but not IL-10, induced by IFN-alpha attenuated IFN-alpha-mediated signaling in myeloma cells via an upregulated SOCS3. Using reverse transcription-polymerase chain reaction, expression of the IL-6 gene (IL-6) and IL-10 was detected in two and three of eight myeloma cell lines, respectively. When myeloma cells were cultured with IFN-alpha, an increase of IL-6 and IL-10 production was detected in IL-6-expressing and in IL-10-expressing cells, respectively. IFN-alpha inhibited the cell growth of these myeloma lines. Addition of an IL-6-neutralizing antibody prolonged the phosphorylation of STAT1 induced by IFN-alpha and significantly enhanced the cell growth suppression of IFN-alpha on IL-6-expressing cells. However, a similar blocking of IL-10 in the presence of IFN-alpha did not affect the growth/survival of IL-10-expressing cells. Interestingly, exogenous IL-6, but not IL-10, induced high levels of SOCS3 expression. Although upregulation of SOCS3 was also observed in the presence of IFN-alpha alone in IL-6-expressing cells, this expression was completely abrogated by the IL-6-neutralizing antibody. The L929 cell line transfected with SOCS3 showed the protection from the growth suppression of IFN-alpha. These results suggest that IL-6 induced by IFN-alpha plays an important role in the growth/survival of myeloma cells via an autocrine loop, and upregulated SOCS3 by IL-6 may be at least partially responsible for the IL-6-mediated inhibition of IFN-alpha signaling in myeloma cells.
α干扰素（IFN-α）被用于治疗多发性骨髓瘤，但其临床效果仍存在争议。在此，我们研究了IFN-α是否改变白细胞介素-6（IL-6）或IL-10的自分泌产生，这两种细胞因子均被确定为调节骨髓瘤细胞生长/存活的关键细胞因子，并发现IFN-α诱导产生的IL-6而非IL-10，通过上调的细胞因子信号转导抑制因子3（SOCS3）减弱了IFN-α介导的骨髓瘤细胞信号传导。使用逆转录-聚合酶链反应，在8个骨髓瘤细胞系中的2个和3个中分别检测到了IL-6基因（IL-6）和IL-10的表达。当骨髓瘤细胞与IFN-α一起培养时，在表达IL-6的细胞和表达IL-10的细胞中分别检测到IL-6和IL-10产生增加。IFN-α抑制了这些骨髓瘤细胞系的细胞生长。添加IL-6中和抗体可延长IFN-α诱导的信号转导和转录激活因子1（STAT1）的磷酸化，并显著增强IFN-α对表达IL-6细胞的细胞生长抑制作用。然而，在IFN-α存在的情况下对IL-10进行类似阻断并不影响表达IL-10细胞的生长/存活。有趣的是，外源性IL-6而非IL-10诱导了高水平的SOCS3表达。尽管在仅存在IFN-α的情况下，在表达IL-6的细胞中也观察到了SOCS3的上调，但这种表达被IL-6中和抗体完全消除。转染了SOCS3的L929细胞系显示出对IFN-α生长抑制的抗性。这些结果表明，IFN-α诱导产生的IL-6通过自分泌环在骨髓瘤细胞的生长/存活中起重要作用，并且IL-6上调的SOCS3可能至少部分负责IL-6介导的骨髓瘤细胞中IFN-α信号传导的抑制。
