Involvement of Thioredoxin in Rheumatoid Arthritis: Its Costimulatory Roles in the TNF-α-Induced Production of IL-6 and IL-8 from Cultured Synovial Fibroblasts

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Abstract
Thioredoxin (TRX) is a cellular reducing catalyst induced by oxidative stress and is involved in the redox regulation of transcription factors such as NF-κB. We found that the serum TRX concentration was elevated in patients with rheumatoid arthritis (RA) as compared with values from healthy individuals and patients with osteoarthritis (33.6 ± 35.1 vs 11.8 ± 6.6 ng/ml, p < 0.01). Moreover, the TRX concentration in the synovial fluid (SF) was much more elevated in RA patients than in osteoarthritis patients (103.4 ± 53.3 vs 24.6 ± 17.4 ng/ml, p < 0.001). Multiple regression analysis revealed that the serum C-reactive protein value was better correlated with the linear combination of SF TNF-α and SF TRX values than with SF TNF-α alone, suggesting that TRX might play a subsidiary role in the rheumatoid inflammation. We thus examined the effect of TRX on the TNF-α-induced IL-6 and IL-8 production using rheumatoid synovial fibroblast cultures. The extents of IL-6 and IL-8 production in response to TNF-α were greatly augmented by TRX as compared with TNF-α alone. TRX alone did not have such effects. We also found that TRX appeared to accelerate the nuclear translocation of NF-κB, a major transcriptional regulator for production of IL-6 and IL-8 on stimulation with TNF-α. Consistent with these findings, the IκBα phosphorylation at Ser32 and its subsequent degradation in response to TNF-α was facilitated by TRX. These findings indicate that the elevated TRX concentration in SF of RA patients might be involved in the aggravation of rheumatoid inflammation by augmenting the NF-κB activation pathway.