Abstract
Objective: Injection of agonistic anti-Fas antibody was shown to decrease disease symptoms in arthritic mouse models. Additionally, membrane bound FasL is able to induce cell death in fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. However, levels of soluble FasL are increased in the joint of RA patients and were associated with disease severity. These results indicate that membrane-bound and soluble FasL have opposing roles in RA and we therefore analyzed the effect of FasL on RA FLS responses. Methods: In the present study, we analyzed the responses of FLS from RA and OA patients to soluble and oligomeric FasL, the latter mimicking membrane-anchored FasL. For this, we used three different FasL variants. In addition, we characterized the signaling pathways triggering FasL-responses. Results: We found that membrane-bound and soluble FasL have distinct roles on RA FLS, as crosslinked FasL preferentially induces apoptosis, whereas soluble FasL stimulates proliferation. Moreover, we found that soluble FasL activates several signaling pathways in RA FLS such as ERK1/2, PI3K, caspase 8 and JNK, with a prominent role for JNK, as only blockage of this pathway renders FLS more susceptible to FasL induced apoptosis. Finally, crosslinked FasL-induced apoptosis in FLS from OA patients, but soluble FasL failed to stimulate their proliferation. Conclusion: Our findings suggest that soluble FasL is a disease promoter in RA, thus concurring with previous reports describing a tumor-promoting role for FasL. Therefore, blocking of sFasL could be a therapeutic strategy for treatment of RA patients. (c) 2014 American College of Rheumatology.