THE EFFICACY OF PROTEASOME INHIBITOR AM114 ON NF kB SIGNAL TRANSDUCTION PATHWAY IN RHEUMATOID ARTHRITIS

Abstract

Rheumatoid arthritis RA is one of the common autoimmune diseases with chronic inflammatory synovitis with cartilage and bone destruction The proinflammatory cytokine interleukin 1beta IL-1and#946; plays a pivotal role in the pathogenesis of RA by activating NFkB pathway The use of Proteasome inhibitors PI in the treatment of autoimmune disease are still at an early stage Inhibition of proteasome function by PI plays an important role in the induction of apoptotic signals and antiinflammatory responses in macrophages The proteasome inhibitor AM114 is a boronic chalcone derivative exerts anticancer activity The present study has explored the effect of AM114 in comparison with aspirin on NFkB signal transduction pathway in IL1and#946; stimulated macrophages derived from HI RA and THP1 cells. Our results showed that AM114 could decrease the production of proinflammatory cytokines chemokines and MMP13 secreted by IL1and#946; stimulated RA and THP1 cells. In addition AM114 has a capacity to induce macrophage apoptosis It also exerts the stabilization of IkB and prevents NFkB p65 nuclear translocation suggesting that AM114 has potent antiinflammatory activity through its inhibitory effects on cytokines by regulating the NFkB pathway The results of this study suggest the use of AM114 as a therapeutic candidate in inflammatory diseases, such as RA newline