Purpose: Elevated IL-17 produced by Th17 cells was reported to promote myeloma cell growth and inhibit immune function in multiple myeloma (MM). IL-17A was also reported to promote MM growth through IL-17 receptors and enhance adhesion to bone marrow stromal cells (BMSCs). Spleen tyrosine kinase (Syk) influences MM cell survival and migration. Herein we aimed to investigate whether Syk was involved in the regulative role of IL-17A in the viability of MM cells.
Methods: Cell viability was determined using CCK8 assay. The production of cytokine including IL-17A was evaluated with ELISA. Western blotting assay was used to determine protein expression levels of Syk and nuclear factor κB (NF-κB) related molecules. mRNA expression level of RORγt was detected with reverse transcription quantitative polymerase chain reaction.
Results: IL-17Awas highly expressed in MM patients and was able to induce MM cell viability. Following analysis indicated that the effects of IL-17A were mediated by Syk/ nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Immunoprecipitation also indicated that Syk is involved in IL-17A-induced Act1-TRAF6 complex formation and TRAF6 polyubiquitination in MM cells.
Conclusions: Taken together, our study indicated that IL-17A increases MM cell viability through activating NF-κB signal pathway via positively regulating Syk expression. Syk also participates in the formation of IL-17R-proximal signaling complex (IL-17R-Act1-TRAF6), which is essential for IL-17A-mediated NF-kB activation. These investigations highlight that inhibition of Syk may be a potential therapeutic option for neoplastic diseases such as MM.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.