Etude des mécanismes contrôlant la prolifération et l'apoptose induite par TRAIL des synoviocytes fibroblastiques dans la polyarthrite rhumatoïde : implication de TRAIL dans la polyarthrite rhumatôïde

Rheumatoid arthritis (RA) is a chronic inflammatory disease. A hallmark of RA is the pseudo-tumoral expansion of fibroblast-like synoviocytes (FLS), as these cells invade and finally destroy the joint structure. RA FLS have been therefore proposed as a therapeutic target. The TNF -related apoptosis-inducing ligand (TRAIL) has been described as a pro-apoptotic factor on malignant cells. The fact that FLS in RA patients exhibit tumor like features led us to investigate the effect of TRAIL on ex-vivo RA FLS. The objective of my PhD has been to clarify the role of TRArL in RA, in particular to study its effect on RA FLS. L have analyzed serum levels of TRAIL and OPG, a solJble TRAIL receptor, in serum from RA patients and observed that a low ratio OPG/TRAIL is associated with better progression of the disease. L could show that TRAIL has a dual effect on RA FLS by inducing cell deCJ. Th and proliferation and that both responses are controlled by caspases. L have also observed that FLS from different-patients have different sensitivities toTRAIL induced apoptosis. To characterize RA FLS of TRAIL on RA FLS sensitive and resistant for TRAIL induced apoptosis l have used biochemical methods and a microarray approach. I found that one TRAIL receptor (TRAIL-R1) and p27 are differentially expressed in resistant and sensitive RA FLS. A microarray analysis displayed that another 13 genes are differentially expressed. Several of these genes are implicated in glycosylation and micro-domains rich in lipids, suggesting that these mechanisms control TRAIL induced cell death in RA FLS. The observation that in RA FLS TRAIL can also trigger signaIs other than apoptosis including proliferation requires to design novel therapeutic approaches based on blocking the proliferative signaling pathwa,ys in order to sensitize tumor cells for TRAIL-induced apoptosis. The proteins/ genes l have identified to be differentially expressed in TRAIL sensitive and resistant RA FLS are therefore potential therapeutic targets