Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production.
OBJECTIVE
Thioredoxin-1 (TRX) is a small multifunctional protein with antioxidative and redox-regulating functions. In this study, we investigated the significance of TRX in patients with inflammatory bowel disease (IBD) and the ability and mechanism to ameliorate experimental colitis.


METHODS
Serum TRX and macrophage migration inhibitory factor (MIF) levels were measured in patients with IBD. The effects of TRX were evaluated in a dextran sulfate sodium (DSS)-induced colitis model by comparing TRX-overexpressing transgenic (TRX-TG) and control mice. We further evaluated the effect of recombinant human TRX (rhTRX) administration on DSS-induced colitis and colonic inflammation of interleukin (IL)-10 knockout (IL-10 KO) mice. Colonic inflammation was examined clinically and histologically. Proinflammatory cytokine levels were examined in colonic tissues, and MIF levels were measured in colonic tissues and sera in mice. The effect of TRX on MIF production was also analyzed in vitro.


RESULTS
Serum TRX and MIF levels were significantly higher in patients with IBD than normal controls, and TRX levels correlated with disease activity. TRX significantly ameliorated DSS-induced colitis and colonic inflammation of IL-10 KO mice. Increase of tumor necrosis factor-alpha and interferon-gamma in colonic tissues was significantly suppressed in TRX-TG mice compared with wild-type mice. MIF levels in colonic tissues and sera were significantly lower in TRX-TG mice than in wild-type mice, irrespective of DSS administration. Anti-TRX treatment exacerbated DSS-induced colitis. In vitro studies demonstrated that rhTRX suppressed MIF production in human monocyte cells.


CONCLUSIONS
TRX might have a potential as a novel therapeutic agent for the treatment of IBD.
Tamaki
Hiroyuki
H
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Nakamura
Hajime
H
Nishio
Akiyoshi
A
Nakase
Hiroshi
H
Ueno
Satoru
S
Uza
Norimitsu
N
Kido
Masahiro
M
Inoue
Satoko
S
Mikami
Sakae
S
Asada
Masanori
M
Kiriya
Keiichi
K
Kitamura
Hiroshi
H
Ohashi
Shinya
S
Fukui
Toshiro
T
Kawasaki
Kimio
K
Matsuura
Minoru
M
Ishii
Yasuyuki
Y
Okazaki
Kazuichi
K
Yodoi
Junji
J
Chiba
Tsutomu
T
D000818:Animals; D000925:Anticoagulants; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D003106:Colon / Q000378:metabolism; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D019746:Intramolecular Oxidoreductases; D007948:Leukemia, Monocytic, Acute; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D013879:Thioredoxins / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000925:Anticoagulants; D007106:Immune Sera; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; C491203:TXN protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D013879:Thioredoxins; D007371:Interferon-gamma; D016264:Dextran Sulfate; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse