Table of Contents Author Guidelines Submit a Manuscript
Mediators of Inflammation
Volume 2013, Article ID 391984, 9 pages
http://dx.doi.org/10.1155/2013/391984
Review Article

Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases

1Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-Ku, Kyoto 606-8507, Japan
2Faculty of Health Science, Suzuka University of Medical Science, Suzuka, Mie, Tsu 510-0293, Japan

Received 12 October 2012; Revised 28 December 2012; Accepted 3 January 2013

Academic Editor: Chiou-Feng Lin

Copyright © 2013 Yuki Murakami et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. H. Munn, E. Shafizadeh, J. T. Attwood, I. Bondarev, A. Pashine, and A. L. Mellor, “Inhibition of T cell proliferation by macrophage tryptophan catabolism,” Journal of Experimental Medicine, vol. 189, no. 9, pp. 1363–1372, 1999. View at Publisher · View at Google Scholar · View at Scopus
  2. A. L. Mellor and D. H. Munn, “Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation?” Immunology Today, vol. 20, no. 10, pp. 469–473, 1999. View at Publisher · View at Google Scholar · View at Scopus
  3. J. A. Ibana, R. J. Belland, A. H. Zea et al., “Inhibition of indoleamine 2,3-dioxygenase activity by levo-1-methyl tryptophan blocks gamma interferon-induced Chlamydia trachomatis persistence in human epithelial cells,” Infection and Immunity, vol. 79, no. 11, pp. 4425–4437, 2011. View at Google Scholar
  4. M. P. Heyes, C. Y. Chen, E. O. Major, and K. Saito, “Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types,” Biochemical Journal, vol. 326, part 2, pp. 351–356, 1997. View at Google Scholar · View at Scopus
  5. G. I. Byrne, L. K. Lehmann, and G. J. Landry, “Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells,” Infection and Immunity, vol. 53, no. 2, pp. 347–351, 1986. View at Google Scholar · View at Scopus
  6. D. H. Munn, M. Zhou, J. T. Attwood et al., “Prevention of allogeneic fetal rejection by tryptophan catabolism,” Science, vol. 281, no. 5380, pp. 1191–1193, 1998. View at Google Scholar · View at Scopus
  7. A. L. Mellor and D. H. Munn, “IDO expression by dendritic cells: tolerance and tryptophan catabolism,” Nature Reviews Immunology, vol. 4, no. 10, pp. 762–774, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. P. Puccetti and U. Grohmann, “IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation,” Nature Reviews Immunology, vol. 7, no. 10, pp. 817–823, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. S. P. Cobbold, E. Adams, C. A. Farquhar et al., “Infectious tolerance via the consumption of essential amino acids and mTOR signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 29, pp. 12055–12060, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. R. Lotfi, J. Eisenbacher, G. Solgi et al., “Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material,” European Journal of Immunology, vol. 41, no. 7, pp. 2021–2028, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. U. Grohmann, F. Fallarino, and P. Puccetti, “Tolerance, DCs and tryptophan: much ado about IDO,” Trends in Immunology, vol. 24, no. 5, pp. 242–248, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. J. B. Katz, A. J. Muller, and G. C. Prendergast, “Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape,” Immunological Reviews, vol. 222, no. 1, pp. 206–221, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. S. Russo, I. P. Kema, M. R. Fokkema et al., “Tryptophan as a link between psychopathology and somatic states,” Psychosomatic Medicine, vol. 65, no. 4, pp. 665–671, 2003. View at Google Scholar
  14. H. J. Yuasa, M. Takubo, A. Takahashi, T. Hasegawa, H. Noma, and T. Suzuki, “Evolution of vertebrate indoleamine 2,3-dioxygenases,” Journal of Molecular Evolution, vol. 65, no. 6, pp. 705–714, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. D. Meininger, L. Zalameda, Y. Liu et al., “Purification and kinetic characterization of human indoleamine 2,3-dioxygenases 1 and 2 (IDO1 and IDO2) and discovery of selective IDO1 inhibitors,” Biochimica et Biophysica Acta, vol. 1814, no. 12, pp. 1947–1954, 2011. View at Google Scholar
  16. H. J. Ball, H. J. Yuasa, C. J. D. Austin, S. Weiser, and N. H. Hunt, “Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 3, pp. 467–471, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. S. Löb, A. Königsrainer, H. G. Rammensee, G. Opelz, and P. Terness, “Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees?” Nature Reviews Cancer, vol. 9, no. 6, pp. 445–452, 2009. View at Google Scholar · View at Scopus
  18. R. Haber, D. Bessette, B. Hulihan-Giblin, M. J. Durcan, and D. Goldman, “Identification of tryptophan 2,3-dioxygenase RNA in rodent brain,” Journal of Neurochemistry, vol. 60, no. 3, pp. 1159–1162, 1993. View at Google Scholar · View at Scopus
  19. C. A. Opitz, U. M. Litzenburger, F. Sahm et al., “An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor,” Nature, vol. 478, no. 7368, pp. 197–203, 2011. View at Google Scholar
  20. C. M. Robinson, P. T. Hale, and J. M. Carlin, “The role of IFN-γ and TNF-α-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase,” Journal of Interferon and Cytokine Research, vol. 25, no. 1, pp. 20–30, 2005. View at Google Scholar · View at Scopus
  21. K. Saito, J. S. Crowley, S. P. Markey, and M. P. Heyes, “A mechanism for increased quinolinic acid formation following acute systemic immune stimulation,” The Journal of Biological Chemistry, vol. 268, no. 21, pp. 15496–15503, 1993. View at Google Scholar · View at Scopus
  22. O. Takikawa, R. Yoshida, R. Kido, and O. Hayaishi, “Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase,” The Journal of Biological Chemistry, vol. 261, no. 8, pp. 3648–3653, 1986. View at Google Scholar · View at Scopus
  23. H. H. Hassanain, S. Y. Chon, and S. L. Gupta, “Differential regulation of human indoleamine 2,3-dioxygenase gene expression by interferons-γ and -α. analysis of the regulatory region of the gene and identification of an interferon-γ-inducible DNA-binding factor,” The Journal of Biological Chemistry, vol. 268, no. 7, pp. 5077–5084, 1993. View at Google Scholar · View at Scopus
  24. S. Y. Chon, H. H. Hassanain, R. Pine, and S. L. Gupta, “Involvement of two regulatory elements in interferon-γ-regulated expression of human indoleamine 2,3-dioxygenase gene,” Journal of Interferon and Cytokine Research, vol. 15, no. 6, pp. 517–526, 1995. View at Google Scholar · View at Scopus
  25. K. V. Konan and M. W. Taylor, “Importance of the two interferon-stimulated response element (ISRE) sequences in the regulation of the human indoleamine 2,3-dioxygenase gene,” The Journal of Biological Chemistry, vol. 271, no. 32, pp. 19140–19145, 1996. View at Publisher · View at Google Scholar · View at Scopus
  26. B. D. Hissong and J. M. Carlin, “Potentiation of interferon-induced indoleamine 2,3-dioxygenase mRNA in human mononuclear phagocytes by lipopolysaccharide and interleukin-1,” Journal of Interferon and Cytokine Research, vol. 17, no. 7, pp. 387–393, 1997. View at Google Scholar · View at Scopus
  27. S. Fujigaki, K. Saito, K. Sekikawa et al., “Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-gamma-independent mechanism,” European Journal of Immunology, vol. 31, no. 8, pp. 2313–2318, 2001. View at Google Scholar
  28. H. Fujigaki, K. Saito, S. Fujigaki et al., “The signal transducer and activator of transcription 1α 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-κB pathways, and synergistic effect of several proinflammatory cytokines,” Journal of Biochemistry, vol. 139, no. 4, pp. 655–662, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Johnson and C. E. Eyers, “Analysis of post-translational modifications by LC-MS/MS,” Methods in Molecular Biology, vol. 658, pp. 93–108, 2010. View at Google Scholar · View at Scopus
  30. N. L. Young, M. D. Plazas-Mayorca, and B. A. Garcia, “Systems-wide proteomic characterization of combinatorial post-translational modification patterns,” Expert Review of Proteomics, vol. 7, no. 1, pp. 79–92, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. H. Fujigaki, K. Saito, F. Lin et al., “Nitration and inactivation of IDO by peroxynitrite,” Journal of Immunology, vol. 176, no. 1, pp. 372–379, 2006. View at Google Scholar · View at Scopus
  32. J. S. Beckman and W. H. Koppenol, “Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly,” American Journal of Physiology, vol. 271, no. 5, part 1, pp. C1424–C1437, 1996. View at Google Scholar · View at Scopus
  33. A. P. Gobert, S. Semballa, S. Daulouede et al., “Murine macrophages use oxygen- and nitric oxide-dependent mechanisms to synthesize S-nitroso-albumin and to kill extracellular trypanosomes,” Infection and Immunity, vol. 66, no. 9, pp. 4068–4072, 1998. View at Google Scholar · View at Scopus
  34. H. Ischiropoulos, L. Zhu, and J. S. Beckman, “Peroxynitrite formation from macrophage-derived nitric oxide,” Archives of Biochemistry and Biophysics, vol. 298, no. 2, pp. 446–451, 1992. View at Publisher · View at Google Scholar · View at Scopus
  35. A. Denicola, H. Rubbo, D. Rodriguez, and R. Radi, “Peroxynitrite-mediated cytotoxicity to Trypanosoma cruzi,” Archives of Biochemistry and Biophysics, vol. 304, no. 1, pp. 279–286, 1993. View at Publisher · View at Google Scholar · View at Scopus
  36. C. Brito, M. Naviliat, A. C. Tiscornia et al., “Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death,” Journal of Immunology, vol. 162, no. 6, pp. 3356–3366, 1999. View at Google Scholar · View at Scopus
  37. S. Yamamoto and O. Hayaishi, “Tryptophan pyrrolase of rabbit intestine. D- and L-tryptophan-cleaving enzyme or enzymes,” The Journal of Biological Chemistry, vol. 242, no. 22, pp. 5260–5266, 1967. View at Google Scholar · View at Scopus
  38. R. Yoshida, Y. Urade, M. Tokuda, and O. Hayaishi, “Induction of indoleamine 2,3-dioxygenase in mouse lung during virus infection,” Proceedings of the National Academy of Sciences of the United States of America, vol. 76, no. 8, pp. 4084–4086, 1979. View at Google Scholar · View at Scopus
  39. H. W. Murray, A. Szuro-Sudol, D. Wellner et al., “Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages,” Infection and Immunity, vol. 57, no. 3, pp. 845–849, 1989. View at Google Scholar · View at Scopus
  40. W. Daubener, K. Pilz, S. Seghrouchni Zennati, T. Bilzer, H. G. Fischer, and U. Hadding, “Induction of toxoplasmostasis in a human glioblastoma by interferon γ,” Journal of Neuroimmunology, vol. 43, no. 1-2, pp. 31–38, 1993. View at Google Scholar · View at Scopus
  41. C. N. Nagineni, K. Pardhasaradhi, M. C. Martins, B. Detrick, and J. J. Hooks, “Mechanisms of interferon-induced inhibition of Toxoplasma gondii replication in human retinal pigment epithelial cells,” Infection and Immunity, vol. 64, no. 10, pp. 4188–4196, 1996. View at Google Scholar · View at Scopus
  42. E. R. Pfefferkorn and P. M. Guyre, “Inhibition of growth of Toxoplasma gondii in cultured fibroblasts by human recombinant gamma interferon,” Infection and Immunity, vol. 44, no. 2, pp. 211–216, 1984. View at Google Scholar · View at Scopus
  43. K. Heseler, K. Spekker, S. K. Schmidt, C. R. MacKenzie, and W. Däubener, “Antimicrobial and immunoregulatory effects mediated by human lung cells: role of IFN-γ-induced tryptophan degradation,” FEMS Immunology and Medical Microbiology, vol. 52, no. 2, pp. 273–281, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. D. H. Munn, M. D. Sharma, D. Hou et al., “Expression of indoleamine 2, 3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes,” The Journal of Clinical Investigation, vol. 114, no. 2, pp. 280–290, 2004. View at Google Scholar
  45. S. K. Schmidt, A. Müller, K. Heseler et al., “Antimicrobial and immunoregulatory properties of human tryptophan 2,3-dioxygenase,” European Journal of Immunology, vol. 39, no. 10, pp. 2755–2764, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Heitger, “Regulation of expression and function of IDO in human dendritic cells,” Current Medicinal Chemistry, vol. 18, no. 15, pp. 2222–2233, 2011. View at Google Scholar · View at Scopus
  47. A. Blaschitz, M. Gauster, D. Fuchs et al., “Vascular endothelial expression of indoleamine 2,3-dioxygenase 1 forms a positive gradient towards the feto-maternal interface,” PLoS ONE, vol. 6, no. 7, Article ID e21774, 2011. View at Publisher · View at Google Scholar · View at Scopus
  48. T. Kaper, L. L. Looger, H. Takanaga, M. Platten, L. Steinman, and W. B. Frommer, “Nanosensor detection of an immunoregulatory tryptophan influx/kynurenine efflux cycle,” PLoS Biology, vol. 5, no. 10, p. e257, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. D. H. Munn, M. D. Sharma, B. Baban et al., “GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase,” Immunity, vol. 22, no. 5, pp. 633–642, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. P. Terness, T. M. Bauer, L. Röse et al., “Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites,” Journal of Experimental Medicine, vol. 196, no. 4, pp. 447–457, 2002. View at Publisher · View at Google Scholar · View at Scopus
  51. F. Fallarino, U. Grohmann, C. Vacca et al., “T cell apoptosis by tryptophan catabolism,” Cell Death and Differentiation, vol. 9, no. 10, pp. 1069–1077, 2002. View at Publisher · View at Google Scholar · View at Scopus
  52. M. L. Belladonna, P. Puccetti, C. Orabona et al., “Immunosuppression via tryptophan catabolism: the role of kynurenine pathway enzymes,” Transplantation, vol. 84, no. 1, supplement, pp. S17–S20, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. F. Fallarino, U. Grohmann, S. You et al., “Tryptophan catabolism generates autoimmune-preventive regulatory T cells,” Transplant Immunology, vol. 17, no. 1, pp. 58–60, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. F. Fallarino, C. Asselin-Paturel, C. Vacca et al., “Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to CD200 receptor engagement,” Journal of Immunology, vol. 173, no. 6, pp. 3748–3754, 2004. View at Google Scholar · View at Scopus
  55. S. Bozza, F. Fallarino, L. Pitzurra et al., “A crucial role for tryptophan catabolism at the host/Candida albicans interface,” Journal of Immunology, vol. 174, no. 5, pp. 2910–2918, 2005. View at Google Scholar · View at Scopus
  56. F. Fallarino and P. Puccetti, “Toll-like receptor 9-mediated induction of the immunosuppressive pathway of tryptophan catabolism,” European Journal of Immunology, vol. 36, no. 1, pp. 8–11, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. U. Grohmann and P. Puccetti, “CTLA-4, T helper lymphocytes and dendritic cells: an internal perspective of T-cell homeostasis,” Trends in Molecular Medicine, vol. 9, no. 4, pp. 133–135, 2003. View at Publisher · View at Google Scholar · View at Scopus
  58. F. Fallarino, U. Grohmann, K. W. Hwang et al., “Modulation of tryptophan catabolism by regulatory T cells,” Nature Immunology, vol. 4, no. 12, pp. 1206–1212, 2003. View at Publisher · View at Google Scholar · View at Scopus
  59. U. Grohmann, R. Bianchi, C. Orabona et al., “Functional plasticity of dendritic cell subsets as mediated by CD40 versus B7 activation,” Journal of Immunology, vol. 171, no. 5, pp. 2581–2587, 2003. View at Google Scholar · View at Scopus
  60. U. Grohmann, F. Fallarino, R. Bianchi et al., “A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice,” Journal of Experimental Medicine, vol. 198, no. 1, pp. 153–160, 2003. View at Publisher · View at Google Scholar · View at Scopus
  61. M. L. Belladonna, C. Volpi, R. Bianchi et al., “Cutting edge: autocrine TGF-β sustains default tolerogenesis by IDO-competent dendritic cells,” Journal of Immunology, vol. 181, no. 8, pp. 5194–5198, 2008. View at Google Scholar · View at Scopus
  62. R. Lande and M. Gilliet, “Plasmacytoid dendritic cells: key players in the initiation and regulation of immune responses,” Annals of the New York Academy of Sciences, vol. 1183, pp. 89–103, 2010. View at Publisher · View at Google Scholar · View at Scopus
  63. B. M. Matta, A. Castellaneta, and A. W. Thomson, “Tolerogenic plasmacytoid DC,” European Journal of Immunology, vol. 40, no. 10, pp. 2667–2676, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. G. Frumento, R. Rotondo, M. Tonetti, G. Damonte, U. Benatti, and G. B. Ferrara, “Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase,” Journal of Experimental Medicine, vol. 196, no. 4, pp. 459–468, 2002. View at Publisher · View at Google Scholar · View at Scopus
  65. S. Okuda, N. Nishiyama, H. Saito, and H. Katsuki, “3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity,” Journal of Neurochemistry, vol. 70, no. 1, pp. 299–307, 1998. View at Google Scholar · View at Scopus
  66. Y. A. Taher, B. J. A. Piavaux, R. Gras et al., “Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model,” Journal of Allergy and Clinical Immunology, vol. 121, no. 4, pp. 983–991, 2008. View at Publisher · View at Google Scholar · View at Scopus
  67. T. Morita, K. Saito, M. Takemura et al., “3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-γ,” Annals of Clinical Biochemistry, vol. 38, part 3, pp. 242–251, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. M. W. Taylor and G. S. Feng, “Relationship between interferon-γ, indoleamine 2,3-dioxygenase, and tryptophan catabolism,” FASEB Journal, vol. 5, no. 11, pp. 2516–2522, 1991. View at Google Scholar · View at Scopus
  69. M. P. Heyes, K. Saito, and S. P. Markey, “Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid,” Biochemical Journal, vol. 283, part 3, pp. 633–635, 1992. View at Google Scholar · View at Scopus
  70. M. P. Heyes, K. Saito, A. Lackner, C. A. Wiley, C. L. Achim, and S. P. Markey, “Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques,” FASEB Journal, vol. 12, no. 10, pp. 881–896, 1998. View at Google Scholar · View at Scopus
  71. Y. Murakami, M. Hoshi, A. Hara et al., “Inhibition of increased indoleamine 2, 3-dioxygenase activity attenuates Toxoplasma gondii replication in the lung during acute infection,” Cytokine, vol. 59, no. 2, pp. 245–251, 2012. View at Google Scholar
  72. L. H. C. Makala, B. Baban, H. Lemos et al., “Leishmania major attenuates host immunity by stimulating local indoleamine 2,3-dioxygenase expression,” Journal of Infectious Diseases, vol. 203, no. 5, pp. 715–725, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Hoshi, K. Saito, A. Hara et al., “The absence of IDO upregulates type I IFN production, resulting in suppression of viral replication in the retrovirus-infected mouse,” Journal of Immunology, vol. 185, no. 6, pp. 3305–3312, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. D. E. Mosier, R. A. Yetter, and H. C. Morse III, “Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice,” Journal of Experimental Medicine, vol. 161, no. 4, pp. 766–784, 1985. View at Google Scholar · View at Scopus
  75. A. Matsumori and C. Kawai, “An experimental model for congestive heart failure after encephalomyocarditis virus myocarditis in mice,” Circulation, vol. 65, no. 6, pp. 1230–1235, 1982. View at Google Scholar · View at Scopus
  76. M. Hoshi, K. Matsumoto, H. Ito et al., “L-tryptophan-kynurenine pathway metabolites regulate type I IFNs of acute viral myocarditis in mice,” Journal of Immunology, vol. 188, no. 8, pp. 3980–3987, 2012. View at Google Scholar
  77. O. Takeuchi and S. Akira, “Innate immunity to virus infection,” Immunological Reviews, vol. 227, no. 1, pp. 75–86, 2009. View at Publisher · View at Google Scholar · View at Scopus
  78. Y. Kumagai, O. Takeuchi, H. Kato et al., “Alveolar macrophages are the primary interferon-alpha producer in pulmonary infection with RNA viruses,” Immunity, vol. 27, no. 2, pp. 240–252, 2007. View at Publisher · View at Google Scholar · View at Scopus
  79. M. D. Sharma, D. Y. Hou, Y. Liu et al., “Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes,” Blood, vol. 113, no. 24, pp. 6102–6111, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. A. K. Manlapat, D. J. Kahler, P. R. Chandler, D. H. Munn, and A. L. Mellor, “Cell-autonomous control of interferon type I expression by indoleamine 2, 3-dioxygenase in regulatory CD19 + dendritic cells,” European Journal of Immunology, vol. 37, no. 4, pp. 1064–1071, 2007. View at Publisher · View at Google Scholar · View at Scopus
  81. W. Cao, S. Manicassamy, H. Tang et al., “Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway,” Nature Immunology, vol. 9, no. 10, pp. 1157–1164, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. P. Bonifazi, C. D'Angelo, S. Zagarella et al., “Intranasally delivered siRNA targeting PI3K/Akt/mTOR inflammatory pathways protects from aspergillosis,” Mucosal Immunology, vol. 3, no. 2, pp. 193–205, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. D. Alberati-Giani and A. M. Cesura, “Expression of the kynurenine enzymes in macrophages and microglial cells: regulation by immune modulators,” Amino Acids, vol. 14, no. 1–3, pp. 251–255, 1998. View at Publisher · View at Google Scholar · View at Scopus
  84. M. D. Sharma, B. Baban, P. Chandler et al., “Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase,” The Journal of Clinical Investigation, vol. 117, no. 9, pp. 2570–2582, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. F. Fallarino, U. Grohmann, and P. Puccetti, “Indoleamine 2, 3-dioxygenase: from catalyst to signaling function,” European Journal of Immunology, vol. 42, no. 8, pp. 1932–1937, 2012. View at Google Scholar
  86. S. Y. Hwang, P. J. Hertzog, K. A. Holland et al., “A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons α and β and alters macrophage responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 24, pp. 11284–11288, 1995. View at Publisher · View at Google Scholar · View at Scopus