Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma

Interleukin-15 (IL-15) induces proliferation and promotes cell survival of human T and B lymphocytes, natural killer cells, and neutrophils, Here we r eport the constitutive expression of a functional IL-15 receptor (IL-15R) i n 6 of 6 myeloma cell lines and in CD38(high)/CD45(low) plasma cells belong ing to 14 of 14 patients with multiple myeloma, Furthermore, we detected IL -15 transcripts in all 6 myeloma cell lines, and IL-15 protein in 4/6 cell lines and also in the primary plasma cells of 8/14 multiple myeloma patient s. Our observations confirm the existence of an autocrine IL-15 loop and po int to the potential paracrine stimulation of myeloma cells by IL-15 releas ed from the cellular microenvironment, Blocking autocrine IL-15 in cell lin es increased the rate of spontaneous apoptosis, and the degree of this effe ct was comparable to the pro-apoptotic effect of depleting autocrine IL-6 b y antibody targeting. IL-15 was also capable of substituting for autocrine IL-6 in order to promote cell survival and vice versa, In short-term cultur es of primary myeloma cells, the addition of IL-15 reduced the percentage o f tumor cells spontaneously undergoing apoptosis. Furthermore, IL-15 lowere d the responsiveness to Fas-induced apoptosis and to cytotoxic treatment wi th vincristine and doxorubicin but not with dexamethasone, These data add I L-15 to the list of important factors promoting survival of multiple myelom a cells and demonstrate that it can be produced and be functionally active in an autocrine manner.