Expression of the thioredoxin-thioredoxin reductase system in the inflamed joints of patients with rheumatoid arthritis.
OBJECTIVE
To examine the expression of the thioredoxin (TRX)-thioredoxin reductase (TR) system in patients with rheumatoid arthritis (RA) and patients with other rheumatic diseases.


METHODS
Levels of TRX in plasma and synovial fluid (SF) were measured using enzyme-linked immunosorbent assay. Cellular distribution of TRX was determined by flow cytometry and histochemistry. Cellular expression of TR was studied by in situ messenger RNA (mRNA) hybridization. The effect of oxidative stress and tumor necrosis factor alpha (TNF alpha) on TRX expression by cultured rheumatoid fibroblast-like synoviocytes was studied.


RESULTS
Significantly increased TRX levels were found in the SF from 22 patients with RA, when compared with plasma levels in the same patients (P < 0.001) and compared with SF TRX levels in 15 patients with osteoarthritis (P < 0.001), 13 patients with gout (P < 0.05), and 9 patients with reactive arthritis (P < 0.0001). The presence of TRX could be demonstrated within the SF-derived mononuclear cells and synovial tissue (ST) of RA patients. Concordantly, expression of TR mRNA was observed in the ST of these patients. Stimulation of synovial fibroblast-like synoviocytes with either H2O2 or TNF alpha induced an increase in the production of TRX.


CONCLUSIONS
The data demonstrate significantly increased concentrations of TRX in the SF and ST of RA patients when compared with the levels in patients with other joint diseases. Evidence is presented that the local environment in the rheumatic joint contributes to increased TRX production. Based on its growth-promoting and cytokine-like properties, it is proposed that increased expression of TRX contributes to the disease activity in RA.
Maurice
M M
MM
Leiden University Hospital, The Netherlands.
Nakamura
H
H
Gringhuis
S
S
Okamoto
T
T
Yoshida
S
S
Kullmann
F
F
Lechner
S
S
van der Voort
E A
EA
Leow
A
A
Versendaal
J
J
Muller-Ladner
U
U
Yodoi
J
J
Tak
P P
PP
Breedveld
F C
FC
Verweij
C L
CL
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013582:Synovial Fluid / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013583:Synovial Membrane / Q000201:enzymology; D013880:Thioredoxin-Disulfide Reductase / Q000096:biosynthesis* / Q000097:blood; D013879:Thioredoxins / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D013880:Thioredoxin-Disulfide Reductase