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 report the constitutive expression of a functional IL-15 receptor (IL-15R) in 6 of 6 myeloma cell lines and in CD38(high)/CD45(low )plasma cells belonging 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 patients. Our observations confirm the existence of an autocrine IL-15 loop and point to the potential paracrine stimulation of myeloma cells by IL-15 released from the cellular microenvironment. Blocking autocrine IL-15 in cell lines increased the rate of spontaneous apoptosis, and the degree of this effect was comparable to the pro-apoptotic effect of depleting autocrine IL-6 by 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 cultures of primary myeloma cells, the addition of IL-15 reduced the percentage of tumor cells spontaneously undergoing apoptosis. Furthermore, IL-15 lowered the responsiveness to Fas-induced apoptosis and to cytotoxic treatment with vincristine and doxorubicin but not with dexamethasone. These data add IL-15 to the list of important factors promoting survival of multiple myeloma cells and demonstrate that it can be produced and be functionally active in an autocrine manner. (Blood. 2000;95:610-618)
Tinhofer
I
I
Laboratory of Molecular Cytology, Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria.
Marschitz
I
I
Henn
T
T
Egle
A
A
Greil
R
R
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D019409:Interleukin-15 / Q000032:analysis / Q000235:genetics* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000032:analysis
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C508024:IL15RA protein, human; D019409:Interleukin-15; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor