Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection
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Altered functions of dendritic cells (DCs) and/or increases of regulatory T cells (Tregs) are involved in the pathogenesis of chronic hepatitis C virus (HCV) infection. A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether or not IDO is activated in chronic hepatitis C patients and its role in immune responses.
This study enrolled 176 patients with chronic HCV infection and 37 healthy volunteers. Serum kynurenine concentration was evaluated by high-performance liquid chromatography, and its correlation with clinical parameters was examined. Monocyte-derived DCs were prepared from the subjects and subsequently stimulated with a combination of lipopolysaccharide and interferon-gamma to induce functional IDO (defined as IDO-DCs). The phenotypes, kynurenine or cytokine production, and T-cell responses with IDO-DCs were compared between the patients and healthy volunteers.
The serum kynurenine level in the patients was significantly higher than that in the healthy volunteers, and the level of serum kynurenine was positively correlated with the histological activity or fibrosis score. IDO activity in IDO-DCs from the patients was significantly higher than that in IDO-DCs from the volunteers. Furthermore, IDO-DCs from the patients induced more Tregs in vitro compared with those from the volunteers, and the frequency of induced Tregs by IDO-DCs was decreased with an IDO-specific inhibitor.
Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.
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- Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection
Journal of Gastroenterology
Volume 48, Issue 5 , pp 660-670
- Cover Date
- Print ISSN
- Online ISSN
- Springer Japan
- Additional Links
- Hepatitis C virus
- Dendritic cell
- Regulatory T cell
- Indoleamine 2,3-dioxygenase
- Industry Sectors
- Koyo Higashitani (1)
- Tatsuya Kanto (1)
- Shoko Kuroda (1)
- Sachiyo Yoshio (1)
- Tokuhiro Matsubara (1)
- Naruyasu Kakita (1)
- Tsugiko Oze (1)
- Masanori Miyazaki (1)
- Mitsuru Sakakibara (2)
- Naoki Hiramatsu (1)
- Eiji Mita (3)
- Yasuharu Imai (4)
- Akinori Kasahara (5)
- Alato Okuno (6)
- Osamu Takikawa (6)
- Norio Hayashi (7)
- Tetsuo Takehara (1)
- Author Affiliations
- 1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
- 2. Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari, Osaka, Japan
- 3. National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo, Osaka, Japan
- 4. Ikeda Municipal Hospital, 3-1-18 Jonan, Ikeda, Osaka, Japan
- 5. Department of General Medicine, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, Japan
- 6. Laboratory of Radiation Safety, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka, Obu, Aichi, Japan
- 7. Kansai Rosai Hospital, 3-1-69 Amagasaki, Hyogo, Japan