Role of protein phosphatase 2A in inflammation and proliferation of fibroblast-like synoviocytes in rheumatoid arthritis

Abstract To understand the effect of protein phosphatase 2A (PP2A) in regulating inflammation and proliferation of fibroblast-like synoviocytes (FLSs) from rheumatoid arthritis (RA), synovial tissues (STs) of osteoarthritis (OA) and RA patients were harvested and FLSs were separated from STs. Several inflammatory factors were applied to stimulate and activate FLSs, which can imitate the process of the inflammatory response in RA FLSs. An inhibitor of PP2A(Okadaic acid) and short interference RNA against PP2A were added to observe that PP2A could influence the inflammation and proliferation of RA FLSs though the ERK and AKT pathways. An agonist of PP2A(FTY720) and lentivirus targeted PP2A were used to investigate that PP2A overexpression could relieve the inflammation and proliferation of RA FLSs. The expression of PP2A and other protein were detected by Western blot and immunohistochemical analysis. The genetic expression of inflammatory factors were measured by real-time polymerase chain reaction. The proliferation of FLSs was detected through the expression of proliferating Cell Nuclear Antigen (PCNA)and cyclin B1. The expression of PP2A in RA STs and FLSs was decreased compared with OA. The level of PP2A was up-regulated in RA FLSs stimulated with TNF-α, IL-1 and lipopolysaccharide(LPS). Inhibition of PP2A by Okadaic acid and special siRNA promoted the inflammation and proliferation of RA FLSs. Furthermore, down-regulation of PP2A increased the phosphorylation level of the ERK and AKT signaling. In addition, FTY720 and lentivirus of PP2A reduced TNF-α, IL-1 and IL-6 production and proliferation of RA FLSs as well as the ERK and AKT pathways. PP2A regulated the inflammatory and proliferation behaviour through the ERK and AKT signaling pathways. Our study suggested that targeting PP2A might a promising therapy to prevent synovial inflammation and destruction.