Smac BV6 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes Activated by TLR9 Ligand
Abstract Rheumatoid arthritis synovial fibroblasts (RASF) are one of the most important cells contributing reumathoid artritis (RA) pathogenesis. The critical role of the Toll-like receptor in inflammation and on autoimmune disease is not fully known. Data rising predominantly from human patients and animal models of autoimmune disease indicate that inappropriate triggering of TLR pathways by exogenous or endogenous ligands may cause the initiation and/or perpetuation of autoimmune reactions and tissue damage. Particularly, the role of TLR9 in RA is still a subject of debate and among TLRs, TLR9 is the only receptor which detects unmethylated CpG motifs in DNA (ODN), and is located intracellularly in endosomes and endoplasmic reticulum. RASFs stimulated by ODN are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. Then, we evaluated the proapoptotic and anti-inflammatory activity of the smac BV6 on RASF cultured in synovial fluid (SF), to reproduce the physiopathological environmental characteristics of RA joints. Furthermore, BV6 induces a significant inhibition of the secretion of IL15, TNF alpha, IL6, stimulation of pannus formation, and damage of bone and cartilage in RA. Moreover the secretion of the anti-inflammatory cytokine IL10 and the cleavage of capase 3 and 8 are dramatically increased in the presence of BV6. Furthermore, TLR9 elicited a robust IFN induction and we reported that in RASF treated with ODN and BV6 the expression of IRF7 is enhanced. Our observations demonstrate that BV6 has beneficial regulatory effects on the inflammatory state induced by TLR9 activation.