Background and aims This study aimed to determine the regulatory role of N-Acetyl-l-cysteine (NAC), an antioxidant, in IL-17-induced osteoclast differentiation in rheumatoid arthritis (RA).
Methods After RA synovial fibroblasts were stimulated by IL-17, the expression and production of RANKL was determined by real-time PCR and ELISA. Human peripheral blood monocytes were cultured with M-CSF, IL-17, RANKL, and/or various concentrations of NAC, followed by counting of the cells for tartrate-resistant acid phosphatase activity to determine osteoclast formation. Osteoclastogenesis was also determined after cocultures of IL-17-stimulated RA synovial fibroblasts, Th17 cells and various concentrations of NAC with monocytes. After human peripheral CD4+ T cells were cultured with NAC under Th17 condition, IL-17, IFN-g, IL-4, Foxp3, RANKL and IL-2 expression and production was determined by flow cytometry or ELISA.
Results When RA synovial fibroblasts were stimulated by IL-17, IL-17 stimulated the production of RANKL, and NAC reduced the IL-17-induced RANKL production in a dose-dependent manner. NAC decreased IL-17-activated phosphorylation of mTOR, JNK and IkB. When human peripheral blood CD14+ monocytes were cultured with M-CSF and IL-17 or RANKL, osteoclasts were differentiated, and NAC reduced the osteoclastogenesis. After human peripheral CD4+ T cells were co-cultured with IL-17-pretreated RA synovial fibroblasts or Th17 cells, NAC reduced their osteoclastogenesis. Under Th17 polarising condition, NAC decreased Th17 cell differentiation and IL-17 and RANKL production.
Conclusions NAC inhibits the IL-17-induced RANKL production in RA synovial fibroblasts and IL-17-induced osteoclast differentiation. NAC also reduced Th17 polarisation. NAC could be a supplementary therapeutic option for inflammatory and bony destructive processes in RA.
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