title: Targeting the Fas/FasL system in Rheumatoid Arthritis therapy: Promising or risky?
abstract: Rheumatoid Arthritis (RA) is a chronic inflammatory disease affecting synovial joints. Tumor necrosis factor (TNF) α is a key component of RA pathogenesis and blocking this cytokine is the most common strategy to treat the disease. Though TNFα blockers are very efficient, one third of the RA patients are unresponsive or present side effects. Therefore, the development of novel therapeutic approaches is required. RA pathogenesis is characterized by the hyperplasia of the synovium, closely associated to the pseudo-tumoral expansion of fibroblast-like synoviocytes (FLS), which invade and destroy the joint structure. Hence, depletion of RA FLS has been proposed as an alternative therapeutic strategy. The TNF family member Fas ligand (FasL) was reported to trigger apoptosis in FLS of arthritic joints by binding to its receptor Fas and therefore suggested as a promising candidate for targeting the hyperplastic synovial tissue. However, this cytokine is pleiotropic and recent data from the literature indicate that Fas activation might have a disease-promoting role in RA by promoting cell proliferation. Therefore, a FasL-based therapy for RA requires careful evaluation before being applied. In this review we aim to overview what is known about the apoptotic and non-apoptotic effects of Fas/FasL system and discuss its relevance in RA.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, Université Montpellier Sud de France, 1919 route de Mende, CNRS, UMR5535, Montpellier, France. Electronic address: flaviach@gmail.com.
authors.forename: Flavia
authors.initials: F
authors.lastname: Calmon-Hamaty
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, Université Montpellier Sud de France, 1919 route de Mende, CNRS, UMR5535, Montpellier, France. Electronic address: rachel.audo@igmm.cnrs.fr.
authors.forename: Rachel
authors.initials: R
authors.lastname: Audo
authors.affiliation: Department of Immuno-Rheumatology, Hôpital Lapeyronie, University of Montpellier 1, Montpellier, France. Electronic address: b-combe@chu-montpellier.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Combe
authors.affiliation: Department of Immuno-Rheumatology, Hôpital Lapeyronie, University of Montpellier 1, Montpellier, France; Institut de Génétique Moléculaire de Montpellier, Université Montpellier Sud de France, 1919 route de Mende, CNRS, UMR5535, Montpellier, France. Electronic address: j-morel@chu-montpellier.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Morel
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, Université Montpellier Sud de France, 1919 route de Mende, CNRS, UMR5535, Montpellier, France; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: hahne@igmm.cnrs.fr.
authors.forename: Michael
authors.initials: M
authors.lastname: Hahne
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000819:agonists / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000166:cytology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000819:agonists / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor
keywords: Apoptosis; Fas ligand; Fibroblast-like synoviocytes; Proliferation; Rheumatoid Arthritis