Presentation: Analysis of TWEAK Stimulation of Synovial Fibroblasts from RA and OA Patients (2007)

155 Analysis of TWEAK Stimulation of Synovial Fibroblasts from RA and OA Patients

Synovial fibroblasts are critically involved in propagating joint inflammation in rheumatoid arthritis (RA) through the production of numerous arthritogenic mediators. The proinflammatory TNF ligand superfamily cytokine TWEAK has previously been shown to induce several chemokine/cytokines in human fibroblast cell types including synovciocytes. In this study, we seek to understand the involvement of TWEAK in human RA pathogenesis by studying its broad effect on human synovial fibroblasts.
The effect of TWEAK (alone and in conjunction with TNF) on synoviocytes from RA and OA patients was analyzed by ELISA, qunatitative PCR and transcription profiling using Affymetrix technology.
Results: Our initial analysis using synviocytes derived from a few patients have revealed that TWEAK regulates the expression of a large panel of genes in human synovial fibroblasts and is a strong inducer of arthritogenic mediators in human synovial fibroblasts, including RANTES, IL-8, IL-6 and IL-1. Interestingly, TWEAK seems to also modulate the proliferative and survival properties of synovial fibroblasts isolated from RA, but not OA patients. It is also worth noting that stimulation effect of synovial fibroblast cells by TWEAK and TNF can be heterogeneous even amongst different RA patients, possibly reflecting the hetergeneous nature of this disease. Importantly, although TWEAK and TNF do not induce the expression of each other, TWEAK and TNF often additively or synergistic stimulate the production of a number cytokines and chemokines such as RANTES.
Conclusion: Traditionally TNF is considered a key driver of joint inflammation through its stimulatory effect of synovial fibroblast. Our results suggest that TWEAK is also an important stimulator of synovial fibroblasts, regulating their proliferative and inflammatory responses. These findings are consistent with the notion that TWEAK might an attractive therapeutic target for the treatment of RA.

  T.S. Zheng, Biogen Idec, Inc., 1; Biogen Idec, Inc., 3; S. Weng, Biogen Idec, 1; Biogen Idec, 3; S. Szak, Biogen Idec, 1; Biogen Idec, 3; L. Burkly, Biogen Idec, 1; Biogen Idec, 3; N. Allair, Biogen Idec, 1; Biogen Idec, 3; D. Lee, None.