Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production.

Abstract

BACKGROUND & AIMS:

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.

• Authors: Hiroyuki Tamaki, Hajime Nakamura, Akiyoshi Nishio, Hiroshi Nakase, Satoru Ueno, Norimitsu Uza, Masahiro Kido, Satoko Inoue, Sakae Mikami, Masanori Asada, Keiichi Kiriya, Hiroshi Kitamura, Shinya Ohashi, Toshiro Fukui, Kimio Kawasaki, Minoru Matsuura, Yasuyuki Ishii, Kazuichi Okazaki, Junji Yodoi, Tsutomu Chiba
• Journal: Gastroenterology (Gastroenterology) Vol. 131 Issue 4 Pg. 1110-21 (Oct 2006) ISSN: 0016-5085 [Print] United States
• PMID: 17030181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticoagulants
• Immune Sera
• Macrophage Migration-Inhibitory Factors
• Recombinant Proteins
• TXN protein, human
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Thioredoxins
• Interferon-gamma
• Dextran Sulfate
• Intramolecular Oxidoreductases
• Mif protein, mouse

Topics

• Animals
• Anticoagulants
• Cell Line, Tumor
• Colitis, Ulcerative (blood, chemically induced, drug therapy, immunology)
• Colon (metabolism)
• Crohn Disease (blood, drug therapy, immunology)
• Dextran Sulfate
• Disease Models, Animal
• Female
• Gene Expression
• Humans
• Immune Sera (pharmacology)
• Interferon-gamma (metabolism)
• Interleukin-10 (genetics)
• Intramolecular Oxidoreductases
• Leukemia, Monocytic, Acute
• Macrophage Migration-Inhibitory Factors (blood)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (drug effects, immunology)
• Oxidation-Reduction
• Oxidative Stress (drug effects, physiology)
• Recombinant Proteins (immunology, pharmacology)
• Thioredoxins (blood, genetics, pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)