Involvement of thioredoxin in rheumatoid arthritis: Its costimulatory roles in the TNF-alpha-induced production of IL-6 and IL-8 from cultured synovial fibroblasts

Thioredoxin (TRX) is a cellular reducing catalyst induced by oxidative stre ss and is involved in the redox regulation of transcription factors such as NF-KB, We found that the serum TRX concentration was elevated in patients with rheumatoid arthritis (RA) as compared with values from healthy individ uals 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 rev ealed that the serum C-reactive protein value was better correlated with th e linear combination of SF TNF-alpha and SF TRX values than with SF TNF-alp ha alone, suggesting that TRX might play a subsidiary role in the rheumatoi d inflammation. We thus examined the effect of TRX on the TNF-alpha-induced IL-6 and IL-8 production using rheumatoid synovial fibroblast cultures. Th e extents of IL-6 and IL-8 production in response to TNF-alpha were greatly augmented by TRX as compared with TNF-alpha alone. TRX alone did not have such effects, We also found that TRX appeared to accelerate the nuclear tra nslocation of NF-KB, a major transcriptional regulator for production of IL -6 and IL-8 on stimulation with TNF-alpha. Consistent with these findings, the I kappa B alpha phosphorylation at Ser(32) and its subsequent degradati on in response to TNF-alpha 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-kappa B activation pathway.