Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt

Abstract : A hallmark of rheumatoid arthritis ( RA) is the pseudotumoral expansion of fibroblast- like synoviocytes ( FLSs), and the RA FLS has therefore been proposed as a therapeutic target. Tumor necrosis factor ( TNF)- related apoptosis- inducing ligand ( TRAIL) has been described as a pro- apoptotic factor on RA FLSs and, therefore, suggested as a potential drug. Here we report that exposure to TRAIL- induced apoptosis in a portion ( up to 30%) of RA FLSs within the first 24 h. In the cells that survived, TRAIL induced RA FLS proliferation in a dose-dependent manner, with maximal proliferation observed at 0.25 nM. This was blocked by a neutralizing anti- TRAIL antibody. RA FLSs were found to express constitutively TRAIL receptors 1 and 2 ( TRAIL- R1 and TRAIL- R2) on the cell surface. TRAIL- R2 appears to be the main mediator of TRAIL- induced stimulation, as RA FLS proliferation induced by an agonistic anti-TRAIL- R2 antibody was comparable with that induced by TRAIL. TRAIL activated the mitogen- activated protein kinases ERK and p38, as well as the phosphatidylinositol 3- kinase ( PI3K)/ Akt signaling pathway with kinetics similar to those of TNF-alpha. Moreover, TRAIL-induced RA FLS proliferation was inhibited by the protein kinase inhibitors PD98059, SB203580, and LY294002, confirming the involvement of the ERK, p38, and PI3 kinase/ Akt signaling pathways. This dual functionality of TRAIL in stimulating apoptosis and proliferation has important implications for its use in the treatment of RA.
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Submitted on : Friday, August 2, 2019 - 11:04:55 AM
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J. Morel, R. Audo, M. Hahne, B. Combe. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. Journal of Biological Chemistry, 2005, 280 (16), pp.15709--15718. ⟨hal-02262258⟩

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