Pereno R, Giron-Michel J, Gaggero A, Cazes E, Meazza R, Monetti M, Monaco E, Mishal Z, Jasmin C, Indiveri F, Ferrini S, Azzarone B
U506 INSERM Hôpital Paul Brousse 94807 Villejuif, France.
Oncogene. 2000 Oct 26;19(45):5153-62. doi: 10.1038/sj.onc.1203873.
There are two IL-15 isoforms and eight isoforms for the IL-15Ralpha chain whose biological role is poorly understood. Here, we have analysed the intracellular trafficking of IL-15 and IL-15Ralpha and tried to shed some light on their function(s). In IL-15/GFP CHO transfectants both IL-15 isoforms show nuclear localization. Two melanoma cell lines (MELP and MELREO) spontaneously expressing the IL-15 isoforms, display different intracellular trafficking of the IL-15/IL-15Ralpha complex. In MELP cells only IL-15Ralpha is detected inside the nucleus, whereas IL-15 and IL-15Ralpha assemble at the cell surface and are internalized. Moreover, the transducing molecule TRAF2 co-immunoprecipitates with IL-15Ralpha and may be deflected to TNFRI using anti-IL-15 blocking mAbs and TNF-alpha. By contrast, MELREO cells display IL-15Ralpha and IL-15 nuclear localization but only a partial co-localization of these molecules on the cell surface. In these cells, TRAF2 is strongly associated with IL-15Ralpha and cannot be deflected by any treatment. Since TRAF2 activates the transcription factor NF-kappaB, IL-15 through IL-15Ralpha, could have a role in the control of this pathway. Indeed, anti-IL-15 MaB inhibit the constitutive nuclear localization of NFkappaB and the phosphorylation of its inhibitor Ikappa-Balpha. Thus, IL-15Ralpha controls NF-kappaB activation, however differences in the intracellular trafficking of the IL-15 and/or IL-15Ralpha suggest a different biological role for this complex in MELP versus MELREO cells.
白细胞介素-15（IL-15）有两种亚型，白细胞介素-15受体α链（IL-15Rα）有八种亚型，其生物学作用尚不清楚。在此，我们分析了IL-15和IL-15Rα的细胞内运输情况，并试图阐明它们的功能。在IL-15/绿色荧光蛋白（GFP）转染的中国仓鼠卵巢（CHO）细胞中，两种IL-15亚型均显示出核定位。两种自发表达IL-15亚型的黑色素瘤细胞系（MELP和MELREO），其IL-15/IL-15Rα复合物的细胞内运输情况不同。在MELP细胞中，仅在细胞核内检测到IL-15Rα，而IL-15和IL-15Rα在细胞表面组装并内化。此外，转导分子肿瘤坏死因子受体相关因子2（TRAF2）与IL-15Rα共免疫沉淀，使用抗IL-15阻断单克隆抗体（mAbs）和肿瘤坏死因子-α（TNF-α）可使其偏向肿瘤坏死因子受体I（TNFRI）。相比之下，MELREO细胞显示IL-15Rα和IL-15的核定位，但这些分子在细胞表面仅部分共定位。在这些细胞中，TRAF2与IL-15Rα紧密相关，且任何处理均不能使其偏向。由于TRAF2激活转录因子核因子κB（NF-κB），IL-15通过IL-15Rα可能在该信号通路的调控中发挥作用。实际上，抗IL-15单克隆抗体抑制NF-κB的组成型核定位及其抑制剂IκBα的磷酸化。因此，IL-15Rα控制NF-κB的激活，然而IL-15和/或IL-15Rα细胞内运输的差异表明该复合物在MELP细胞与MELREO细胞中具有不同的生物学作用。
