Skip to main content

Advertisement

SpringerLink
Log in

Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41–52.

    Article  PubMed  CAS  Google Scholar 

  2. Seeff LB. Natural history of chronic hepatitis C. Hepatology. 2002;36:S35–46.

    Article  PubMed  Google Scholar 

  3. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.

    Article  PubMed  CAS  Google Scholar 

  4. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711.

    Article  PubMed  CAS  Google Scholar 

  5. Kanto T, Hayashi N, Takehara T, Tatsumi T, Kuzushita N, Ito A, et al. Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J Immunol. 1999;162:5584–91.

    PubMed  CAS  Google Scholar 

  6. Kanto T, Inoue M, Miyatake H, Sato A, Sakakibara M, Yakushijin T, et al. Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J Infect Dis. 2004;190:1919–26.

    Article  PubMed  Google Scholar 

  7. Bain C, Fatmi A, Zoulim F, Zarski JP, Trepo C, Inchauspe G. Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology. 2001;120:512–24.

    Article  PubMed  CAS  Google Scholar 

  8. Murakami H, Akbar SM, Matsui H, Horiike N, Onji M. Decreased interferon-alpha production and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C. Clin Exp Immunol. 2004;137:559–65.

    Article  PubMed  CAS  Google Scholar 

  9. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.

    Article  PubMed  CAS  Google Scholar 

  10. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, et al. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004;40:1062–71.

    Article  PubMed  CAS  Google Scholar 

  11. Itose I, Kanto T, Kakita N, Takebe S, Inoue M, Higashitani K, et al. Enhanced ability of regulatory T cells in chronic hepatitis C patients with persistently normal alanine aminotransferase levels than those with active hepatitis. J Viral Hepat. 2009;16:844–52.

    Article  PubMed  CAS  Google Scholar 

  12. Yamazaki F, Kuroiwa T, Takikawa O, Kido R. Human indolylamine 2,3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme. Biochem J. 1985;230:635–8.

    PubMed  CAS  Google Scholar 

  13. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4:762–74.

    Article  PubMed  CAS  Google Scholar 

  14. Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 1991;5:2516–22.

    PubMed  CAS  Google Scholar 

  15. Puccetti P. On watching the watchers: IDO and type I/II IFN. Eur J Immunol. 2007;37:876–9.

    Article  PubMed  CAS  Google Scholar 

  16. Braun D, Longman RS, Albert ML. A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood. 2005;106:2375–81.

    Article  PubMed  CAS  Google Scholar 

  17. Boasso A, Herbeuval JP, Hardy AW, Anderson SA, Dolan MJ, Fuchs D, et al. HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood. 2007;109:3351–9.

    Article  PubMed  CAS  Google Scholar 

  18. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–3.

    Article  PubMed  CAS  Google Scholar 

  19. Hainz U, Jurgens B, Heitger A. The role of indoleamine 2,3-dioxygenase in transplantation. Transpl Int. 2007;20:118–27.

    Article  PubMed  CAS  Google Scholar 

  20. Platten M, Ho PP, Youssef S, Fontoura P, Garren H, Hur EM, et al. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science. 2005;310:850–5.

    Article  PubMed  CAS  Google Scholar 

  21. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9:1269–74.

    Article  PubMed  CAS  Google Scholar 

  22. Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science. 2002;297:1867–70.

    Article  PubMed  CAS  Google Scholar 

  23. Terness P, Bauer TM, Rose L, Dufter C, Watzlik A, Simon H, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med. 2002;196:447–57.

    Article  PubMed  CAS  Google Scholar 

  24. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008;181:5396–404.

    PubMed  CAS  Google Scholar 

  25. Jurgens B, Hainz U, Fuchs D, Felzmann T, Heitger A. Interferon-gamma-triggered indoleamine 2,3-dioxygenase competence in human monocyte-derived dendritic cells induces regulatory activity in allogeneic T cells. Blood. 2009;114:3235–43.

    Article  PubMed  Google Scholar 

  26. Larrea E, Riezu-Boj JI, Gil-Guerrero L, Casares N, Aldabe R, Sarobe P, et al. Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection. J Virol. 2007;81:3662–6.

    Article  PubMed  CAS  Google Scholar 

  27. Yakushijin T, Kanto T, Inoue M, Oze T, Miyazaki M, Itose I, et al. Reduced expression and functional impairment of Toll-like receptor 2 on dendritic cells in chronic hepatitis C virus infection. Hepatol Res. 2006;34:156–62.

    Article  PubMed  CAS  Google Scholar 

  28. Takikawa O, Yoshida R, Kido R, Hayaishi O. Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J Biol Chem. 1986;261:3648–53.

    PubMed  CAS  Google Scholar 

  29. Suzuki Y, Suda T, Furuhashi K, Suzuki M, Fujie M, Hahimoto D, et al. Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer. 2010;67:361–5.

    Article  PubMed  Google Scholar 

  30. Suh HS, Zhao ML, Rivieccio M, Choi S, Connolly E, Zhao Y, et al. Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3 ligand poly(I:C): mechanism of induction and role in antiviral response. J Virol. 2007;81:9838–50.

    Article  PubMed  CAS  Google Scholar 

  31. Godin-Ethier J, Pelletier S, Hanafi LA, Gannon PO, Forget MA, Routy JP, et al. Human activated T lymphocytes modulate IDO expression in tumors through Th1/Th2 balance. J Immunol. 2009;183:7752–60.

    Article  PubMed  CAS  Google Scholar 

  32. Jung ID, Lee CM, Jeong YI, Lee JS, Park WS, Han J, et al. Differential regulation of indoleamine 2,3-dioxygenase by lipopolysaccharide and interferon gamma in murine bone marrow derived dendritic cells. FEBS Lett. 2007;581:1449–56.

    Article  PubMed  CAS  Google Scholar 

  33. Fujigaki H, Saito K, Fujigaki S, Takemura M, Sudo K, Ishiguro H, et al. The signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3-dioxygenase by lipopolysaccharide: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways, and synergistic effect of several proinflammatory cytokines. J Biochem. 2006;139:655–62.

    Article  PubMed  CAS  Google Scholar 

  34. Fujigaki S, Saito K, Sekikawa K, Tone S, Takikawa O, Fujii H, et al. Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-gamma-independent mechanism. Eur J Immunol. 2001;31:2313–8.

    Article  PubMed  CAS  Google Scholar 

  35. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633–42.

    Article  PubMed  CAS  Google Scholar 

  36. Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci USA. 2009;106:12055–60.

    Article  PubMed  CAS  Google Scholar 

  37. Li R, Perez N, Karumuthil-Melethil S, Prabhakar BS, Holterman MJ, Vasu C. Enhanced engagement of CTLA-4 induces antigen-specific CD4+CD25+Foxp3+ and CD4+CD25− TGF-beta 1+ adaptive regulatory T cells. J Immunol. 2007;179:5191–203.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded in part by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan and the Ministry of Education, Science and Culture of Japan (ID 22590729 and 22590730).

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan

    Koyo Higashitani, Tatsuya Kanto, Shoko Kuroda, Sachiyo Yoshio, Tokuhiro Matsubara, Naruyasu Kakita, Tsugiko Oze, Masanori Miyazaki, Naoki Hiramatsu & Tetsuo Takehara

  2. Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari, Osaka, Japan

    Mitsuru Sakakibara

  3. National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo, Osaka, Japan

    Eiji Mita

  4. Ikeda Municipal Hospital, 3-1-18 Jonan, Ikeda, Osaka, Japan

    Yasuharu Imai

  5. Department of General Medicine, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, Japan

    Akinori Kasahara

  6. Laboratory of Radiation Safety, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka, Obu, Aichi, Japan

    Alato Okuno & Osamu Takikawa

  7. Kansai Rosai Hospital, 3-1-69 Amagasaki, Hyogo, Japan

    Norio Hayashi

Authors
  1. Koyo Higashitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatsuya Kanto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shoko Kuroda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sachiyo Yoshio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tokuhiro Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naruyasu Kakita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tsugiko Oze
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masanori Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mitsuru Sakakibara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Naoki Hiramatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eiji Mita
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yasuharu Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Akinori Kasahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alato Okuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Osamu Takikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Norio Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tetsuo Takehara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatsuya Kanto.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figures (PDF 144 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Higashitani, K., Kanto, T., Kuroda, S. et al. Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection. J Gastroenterol 48, 660–670 (2013). https://doi.org/10.1007/s00535-012-0667-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-012-0667-z

Keywords

Search

Navigation