IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα

There are two IL-15 isoforms and eight isoforms for the IL-15R alpha chain whose biological role is poorly understood. Here, we have analysed the intracellular trafficking of IL-15 and IL-15R alpha 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-15R alpha complex, In MELP cells only IL-15R alpha is detected inside the nucleus, whereas IL-15 and IL-15R alpha assemble at the cell surface and are internalized, Moreover, the transducing molecule TRAF2 co-immunoprecipitates with IL-15R alpha and may be deflected to TNFRI using anti-IL-15 blocking mAbs and TNF-alpha, By contrast, MELREO cells display IL-15R alpha 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-15R alpha and cannot be deflected by any treatment, Since TRAF2 activates the transcription factor NF-kappaB, IL-15 through IL-15R alpha, could have a role in the control of this pathway. Indeed, anti-IL-15 MaB inhibit the constitutive nuclear localization of NF kappaB and the phosphorylation of its inhibitor I kappa -B alpha, Thus, IL-15R alpha controls NF-KB activation, however differences in the intracellular trafficking of the IL-15 and/or IL-15R alpha suggest a different biological role for this complex in MELP versus MELREO cells.