Inhibition of TNF-induced IL-6 by the TWEAK-Fn14 interaction in rheumatoid arthritis fibroblast like synoviocytes.

Objectives: TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, has been shown to increase cytokine production by rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). In this study, we determined the effect of interaction between TWEAK and its receptor fibroblast growth factor-inducible-14 (Fn14) on cytokine expression in RAFLS. Method(s): RAFLS were obtained from surgical synovial specimens and used at passage 5-10. Cytokine protein and mRNA expression were measured with ELISA and real time-PCR, respectively. Apoptotic cells were detected by TUNEL assay. RelB activation was detected by Western blot analysis. Result(s): TWEAK inhibited IL-6 production from total synovial cells from RA. TWEAK weakly induced FLS IL-6 and IL-8, but in contrast TWEAK dose-dependently inhibited IL-6 and IL-8 production by TNFalpha-activated FLS. TWEAK did not induce apoptosis in FLS but inhibited proliferation of TNFalpha-activated FLS. TWEAK induced RelB activation and suppressed IL-6 mRNA expression in TNFalpha-activated FLS and both of these phenomenon were abolished by inhibition of new protein synthesis with cycloheximide. Conclusion(s): TWEAK has a previously unsuspected inhibitory effect on cytokine production by TNFalpha-activated RAFLS. This observation suggests that the effects of TWEAK on cytokine expression varies with the pro-inflammatory context, and that in TNFalpha-activated states such as RA TWEAK may have a net inhibitory effect. © 2011 Elsevier Inc.