title: Distinct effects of soluble and membrane-bound fas ligand on fibroblast-like synoviocytes from rheumatoid arthritis patients.
abstract: OBJECTIVE
  Injection of agonistic anti-Fas antibody has been shown to decrease disease symptoms in mouse models of arthritis. Additionally, membrane-bound FasL (mFasL) has been shown to induce cell death in fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. However, levels of soluble FasL (sFasL) are increased in the joints of RA patients and have been associated with disease severity, indicating that mFasL and sFasL play opposing roles in RA. The purpose of this study was to analyze the effects of FasL on RA FLS responses.
  
  
  METHODS
  The responses of FLS from RA and osteoarthritis (OA) patients to soluble and oligomeric FasL, the latter mimicking mFasL, were analyzed by fluorescence-activated cell sorting and proliferation assays, using 3 different FasL variants. The signaling pathways that trigger FasL responses were characterized by Western blotting.
  
  
  RESULTS
  We found that mFasL and sFasL have distinct roles in RA FLS. Crosslinked FasL preferentially induced apoptosis, whereas sFasL stimulated proliferation. Moreover, sFasL activated several signaling pathways in RA FLS, such as ERK-1/2, phosphatidylinositol 3-kinase, caspase 8, and JNK, with a prominent role of JNK, since only the blockade of this pathway rendered FLS more susceptible to FasL-induced apoptosis. Crosslinked FasL induced apoptosis in FLS from OA patients, but sFasL failed to stimulate their proliferation.
  
  
  CONCLUSIONS
  Our findings suggest that sFasL is a disease promoter in RA, a finding consistent with previous reports describing a tumor-promoting role of FasL. Therefore, blocking of sFasL could be a therapeutic strategy for RA.
authors: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, Université Montpellier Sud de France, Montpellier 1 University, and Lapeyronie Teaching Hospital, Montpellier, France.
authors: Rachel
authors: R
authors: Audo
authors: Flavia
authors: F
authors: Calmon-Hamaty
authors: Laura
authors: L
authors: Papon
authors: Bernard
authors: B
authors: Combe
authors: Jacques
authors: J
authors: Morel
authors: Michael
authors: M
authors: Hahne
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D019869:Phosphatidylinositol 3-Kinases