TWEAK differentially regulates the production of inflammatory mediators from fibroblast‐like synoviocytes of rheumatoid arthritis

Abstract

Objectives: To investigate the regulatory role of TWEAK on production of effector molecules from fibroblast‐like synoviocytes (FLS) in rheumatoid arthritis (RA).Methods: The expression of TWEAK and Fn14 was evaluated using immunohistochemical study. After stimulation of FLS with TWEAK, gene expression microarray assay was performed. The expression of Fn14 and effector molecules was determined by RT‐PCR, Western blot analysis, and flow cytometry. Results: The expression of TWEAK and Fn14 was up‐regulated within synovial tissues of RA. The expression of Fn14 on the FLS was induced by PMA but not by FGF‐acidic or ‐basic. When the expression gene profile was evaluated, transcripts of MMPs were down‐regulated with TWEAK treatment. To confirm the results, FLS was stimulated with soluble TWEAK (100ng/ml), which increased ICAM‐1 and VCAM‐1, but down‐regulated MMP‐1 and TIMP‐1 slightly. TWEAK showed an additive effect on IL‐1¥â‐ and IFN‐¥ã‐induced up‐regulation of ICAM‐1 & VCAM‐1, but no additional effects on the TNF‐¥á‐induced up‐regulation. TWEAK significantly inhibited IL‐1¥â‐induced production of MMP‐1 and TIMP‐1. Although COX‐2 expression was highly upregulated by IL‐1¥â, Tweak did not make any additional changes. Conclusions: Our data showed that the interaction between TWEAK and Fn14 may involve in the pathogenesis of RA by differentially regulating the synthesis of effector molecules from FLS.