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-Induced Production of IL-6 and IL-8 from Cultured Synovial Fibroblasts1



Departments of
*
Molecular Genetics and
Orthopedics, Nagoya City University Medical School, Nagoya, Japan; and
Louis Pasteur Center for Medical Research, Kyoto, Japan
Thioredoxin (TRX) is a cellular reducing catalyst induced by
oxidative stress and is involved in the redox regulation of
transcription factors such as NF-
B. 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-
and SF TRX values than with SF TNF-
alone, suggesting that TRX might play a subsidiary role in the
rheumatoid inflammation. We thus examined the effect of TRX on the
TNF-
-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-
were greatly augmented by TRX as compared with
TNF-
alone. TRX alone did not have such effects. We also found that
TRX appeared to accelerate the nuclear translocation of NF-
B, a
major transcriptional regulator for production of IL-6 and IL-8 on
stimulation with TNF-
. Consistent with these findings, the I
B
phosphorylation at Ser32 and its subsequent degradation in
response to TNF-
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-
B activation pathway.
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