Piceatannol suppresses inflammation and promotes apoptosis in rheumatoid arthritis-fibroblast-like synoviocytes by inhibiting the NF-κB and MAPK signaling pathways

Abstract

Rheumatoid arthritis (RA) is a chronic inflamma- tory disease that mainly targets the synovial membrane, thus causing stiffness, deformity and dysfunction of joints. To date, no effective anti-inflammatory treatments are available for RA. Piceatannol (PIC) is a natural derivative of resveratrol, which has been reported to attenuate the inflammatory response. To evaluate the effect of PIC on RA and to determine the underlying molecular target of PIC, both in vitro and in vivo experiments were performed in the present study. A CIA rat model was established to evaluate the therapeutic effects of PIC. TNF-a, IL-1β and IL-6 levels in blood were measured by ELISA. Western blotting, immunofluorescence analysis and reverse transcription-quantitative PCR (RT-qPCR) were used to analyze the expression levels of protein and mRNA. In vitro, RA-fibroblast-like synoviocytes (FLSs) were pretreated with PIC and subsequently stimulated with TNF-a. The results revealed that PIC significantly upregulated the expression levels of proapoptotic proteins such as Bax and cleaved caspase-3. PIC also significantly reduced the production of proinflammatory cytokines, including PGE2, IL-6 and IL-1β, and significantly downregulated the expression of cyclo- oxygenase-2 at both the mRNA and protein expression levels. Furthermore, PIC downregulated the expression of MMP-3 and MMP-13, which have been found to be highly expressed in the synovium of patients with RA. Mechanistically, PIC was capable of significantly downregulating the expression levels of proteins involved in the NF-κB and MAPK signaling pathways. The results of the in vivo experiments using a rat collagen-induced arthritis model demonstrated that PIC decreased the arthritis score and exerted beneficial effects in cartilage and significantly reduced the expression of MMP-13. In conclusion, the findings of the present study revealed that PIC could suppress the inflammatory response, promote apop- tosis, and exert a significant regulatory effect on the NF-κB and MAPK signaling pathways in RA-FLSs. Therefore, PIC may represent a potential drug for the future treatment of RA.