Impairment of thioredoxin reductase activity by oxidative stress in human rheumatoid synoviocytes.
The thioredoxin/thioredoxin reductase system is strongly induced in patients with rheumatoid arthritis (RA). We have investigated the impact on TR activity of doses of superoxide anion generated by the hypoxanthine (HX)/xanthine oxidase (XO) system and by hydrogen peroxide, H(2)O(2), for various times and compared the findings with synoviocytes obtained from osteoarthritis (OA) patients. At baseline, TR activity in RA cells was significantly higher than in OA cells (2.31 +/- 0.65 versus 0.74 +/- 0.43 mUnit/mg protein, p < 0.01). HX/XO and H(2)O(2) in RA cells decreased TR activity, which was found to be unchanged in OA cells. H(2)O(2) and superoxide anion caused a time-dependent accumulation of oxidized TR and induced the formation of carbonyl groups in TR protein in RA cells rather than OA cells, and oxidized the selenocysteine of the active site. The oxidation in TR protein was irreversible in RA cells but not in OA cells. In conclusion, we report that the oxidative aggression generates modifications in the redox status of the active site of the TR and induces an alteration of the Trx/TR system, concomitant with those of the other antioxidant systems that could explain the causes of oxidative stress related to RA disease.
Lemarechal
Herve
H
Biochemistry laboratory Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
Anract
Philippe
P
Beaudeux
Jean-Louis
JL
Bonnefont-Rousselot
Dominique
D
Ekindjian
Ovanhesse G
OG
Borderie
Didier
D
D000975:Antioxidants / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019271:Hypoxanthine / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D013583:Synovial Membrane / Q000201:enzymology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D000975:Antioxidants; D016877:Oxidants; D012333:RNA, Messenger; D013481:Superoxides; D019271:Hypoxanthine; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase; D013880:Thioredoxin-Disulfide Reductase