Fucosylation regulates cell death in rheumatoid arthritis (87.24)

Abstract

Abstract Abnormal inflammation and apoptosis are major pathogenic features of synovial fibroblasts (SF) in rheumatoid arthritis (RA). Fucosylation, an important type of glycosylation, has been identified in cancer and inflammation conditions. The role of fucosylation in RA was investigated. Real-time PCR indicated that between RASF and osteoarthritis (OA) SF (N=14 each), there was no difference in the expression of apoptosis related molecules, including tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), its receptors DR4, DR5, DR6, DcR1, DcR2, and regulators of apoptosis FLIPL and cIAPs. However, there was a higher level of α1-2-Fucosyltransferase (Fut1, P=0.016), α1-3/1-4-Fucosyltransferase (Fut3, P=0.018) and α1-3-Fucosyltransferase (Fut6, P=0.038), but not α1-6-Fucosyltransferase (Fut8, P=0.910) in RA compared to OA synovial tissues. Interestingly, a strong positive correlation between TNFα and Fut1, Fut3 and Fut6 was identified. Fut1 also correlated with Il17a. Preincubation of RASFs with 2-Deoxy-D-Galactose (15 mM/ml), a FUT1 inhibitor, decreased the sensitivity to TRA-8, an anti-human DR5 antibody, mediated apoptosis and this effect can be reversed by fucose (15 mM). Similar results were also found on human monocyte/macrophage cell lines, HL60 and THP-1. Our studies suggest that fucosylation is strongly associated with abnormal inflammation and apoptosis in RA effector cells. Fucosylation might be a novel target for RA therapy.