Autophagy inhibitor regulates apoptosis and proliferation of synovial fibroblasts through the inhibition of PI3K/AKT pathway in collagen-induced arthritis rat model

摘要

Background and objective: Mounting studies have illustrated an important role of autophagy in various diseases, but few studies have reported its contribution to rheumatoid arthritis (RA) and the underlying mechanism was largely unknown. This study aimed to investigate whether autophagy inhibitors could regulate apoptosis and proliferation through PI3K/AKT pathway in RA. Methods: RA animal model was established by collagen induction. General observations and degree of joint swelling were observed. Inflammatory response, cell survival related factors and apoptosis were also detected in synovial fibroblasts. In addition, cultured rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) were subjected to TNF-α treatment in vitro, and TNF-α induced cell autophagy, synovial cell proliferation and apoptosis were detected. Moreover, cell cycle and cytokine secretion protein, along with the above parameters, were analyzed. Results: Results from the animal model showed that autophagy inhibitors attenuated inflammatory reaction and synovial hyperplasia, while promoted synovial fibroblasts apoptosis. Meanwhile, inhibition of autophagy promoted cell apoptosis and reversed cell proliferation in vitro, also blocked cell in the G2/M arrest and reduced the S phase cells. Furthermore, we observed that inhibition of PI3K/AKT pathway reversed TNF-α mediated autophagy and cytokine secretion. Conclusion: autophagy inhibitors could mitigate inflammation response, inhibiting RA-FLS cell proliferation while promoting cell apoptosis by the PI3K/AKT pathway.