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

• Published in: Blood Vol. 95; no. 2; pp. 610 - 618
• Main Authors: TINHOFER, I, MARSCHITZ, I, HENN, T, EGLE, A, GREIL, R
• Format: Journal Article
• Language: English
• Published: Washington, DC The Americain Society of Hematology 15.01.2000
• Subjects: Adult; Aged; Apoptosis - drug effects; Apoptosis - immunology; bcl-2-Associated X Protein; Biological and medical sciences; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; Fas Ligand Protein; fas Receptor - analysis; Flow Cytometry; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - pathology; Humans; Interleukin-15 - analysis; Interleukin-15 - genetics; Interleukin-15 - pharmacology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - pathology; Medical sciences; Membrane Glycoproteins - analysis; Middle Aged; Multiple Myeloma - immunology; Multiple Myeloma - pathology; Plasma Cells - immunology; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins c-bcl-2 - analysis; Receptors, Interleukin-15; Receptors, Interleukin-2 - analysis; Receptors, Interleukin-2 - biosynthesis; Receptors, Interleukin-2 - genetics; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Tumor Cells, Cultured; Human; Immunopathology; Autocrine secretion; Immunoglobulinopathy; Lymphoproliferative syndrome; Dissemination; Cytokine; Malignant hemopathy; Metastasis; Interleukin 15; Myeloma; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v95.2.610

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)