IL-21 Stimulates Human Myeloma Cell Growth through an Autocrine IGF-1 Loop

• Published in: The Journal of immunology (1950) 2008-11, Vol.181 (10), p.6837-6842
• Main Authors: Menoret, Emmanuelle, Maiga, Sophie, Descamps, Geraldine, Pellat-Deceunynck, Catherine, Fraslon, Caroline, Cappellano, Melania, Moreau, Philippe, Bataille, Regis, Amiot, Martine
• Format: Article
• Language: English
• Subjects: Autocrine Communication - physiology; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Clone Cells; Flow Cytometry; Fluorescent Antibody Technique; Humans; Insulin-Like Growth Factor I - metabolism; Interleukins - metabolism; Leukocyte Common Antigens - metabolism; Multiple Myeloma - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.10.6837

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.