Interleukin-21 is a growth and survival factor for human myeloma cells.
Interleukin-21 (IL-21) is a recently cloned cytokine with homology to IL-2, IL-4, and IL-15. In this study we examined the effects of IL-21 on human myeloma cells. We found that IL-21 induced proliferation and inhibited apoptosis of the IL-6-dependent human myeloma cell lines ANBL-6, IH-1, and OH-2. The potency of IL-21 was close to that of IL-6 in the OH-2 cell line. Neutralizing antibodies to IL-6 or the IL-6 receptor transducer chain (gp130) did not affect IL-21-induced DNA synthesis, indicating that IL-21-induced proliferation was not mediated through these proteins. Tumor necrosis factor (TNF), another stimulator of myeloma cell growth, up-regulated the expression level of IL-21 receptor (IL-21R), and combinations of TNF and IL-21 gave synergistic effects on myeloma cell proliferation. Furthermore, 4 of 9 purified samples of primary myeloma cells showed a significant increase in DNA synthesis on stimulation of the cells by IL-21. By Western blot analysis, we demonstrated that the intracellular signaling pathways of IL-21 in myeloma cells involved phosphorylation of Jak1, Stat3, and Erk1/2 (p44/42 mitogen-activated protein kinase). IL-21 is a novel growth and survival factor in multiple myeloma and may represent a target for future therapy.
Brenne
Anne-Tove
AT
Department of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway.
Ro
Torstein Baade
TB
Waage
Anders
A
Sundan
Anders
A
Borset
Magne
M
Hjorth-Hansen
Henrik
H
D000368:Aged; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis; D002455:Cell Division; D002470:Cell Survival / Q000187:drug effects; D050822:Cytokine Receptor gp130; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D053738:Interleukin-21 Receptor alpha Subunit; D015850:Interleukin-6 / Q000502:physiology; D007378:Interleukins / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053655:Receptors, Interleukin-21; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000098546:Interleukin-21
D015703:Antigens, CD; D004273:DNA, Neoplasm; D006133:Growth Substances; C508117:IL21R protein, human; C494199:IL6ST protein, human; D053738:Interleukin-21 Receptor alpha Subunit; D015850:Interleukin-6; D007378:Interleukins; D008562:Membrane Glycoproteins; D012334:RNA, Neoplasm; D018123:Receptors, Interleukin; D053655:Receptors, Interleukin-21; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130; D000098546:Interleukin-21