title: IL-21 stimulates human myeloma cell growth through an autocrine IGF-1 loop.
abstract: IL-21 is a member of the type I cytokine family related most closely to IL-2 and IL-15. IL-21 is a pleiotropic cytokine, produced by T, NKT, and dendritic cells, which modulates lymphoid and myeloid cell functions. Besides its activities on normal lymphoid cells, it has been shown that IL-21 is a growth factor for myeloma cells. In the present study, we demonstrate that IL-21 generated myeloma colonies from 9 of 24 human myeloma cell lines (HMCL) in a collagen-based assay. Of major interest, the capacity of IL-21 to stimulate clonogenicity was restricted to CD45(-) HMCL. We found that IL-21 induced tyrosine phosphorylation of STAT-3, STAT-1, and Erk1/2. Interestingly, an Akt activation was observed lately after 30 min to 1 h of IL-21 stimulation, indicating that this Akt phosphorylation could be due to an IGF-1 autocrine loop. This hypothesis was sustained both by the fact that IL-21 treatment induced an IGF-1 mRNA synthesis and that an antagonistic anti-IGF-1 receptor mAb (AVE1642) strongly inhibits the IL-21-induced clonogenicity. Thus, we demonstrated by quantitative PCR that IL-21 induced clonogenicity through an autocrine IGF-1 secretion in HMCL and primary myeloma cells. Because we have previously demonstrated that CD45 phosphatase inhibits the IGF-1 signaling, this inhibitory effect of CD45 explains why the IL-21-induced clonogenicity was restricted to CD45(-) HMCL. These results support that therapy against IGF-1R, which are presently under investigation in multiple myeloma, could be beneficial, not only to suppress IGF-1-mediated myeloma cell growth, but also IL-21-mediated myeloma cell growth.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 892, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Ménoret
authors.forename: Sophie
authors.initials: S
authors.lastname: Maïga
authors.forename: Géraldine
authors.initials: G
authors.lastname: Descamps
authors.forename: Catherine
authors.initials: C
authors.lastname: Pellat-Deceunynck
authors.forename: Caroline
authors.initials: C
authors.lastname: Fraslon
authors.forename: Melania
authors.initials: M
authors.lastname: Cappellano
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.forename: Régis
authors.initials: R
authors.lastname: Bataille
authors.forename: Martine
authors.initials: M
authors.lastname: Amiot
mesh_terms: D019898:Autocrine Communication / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D007334:Insulin-Like Growth Factor I; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D000098546:Interleukin-21