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

Indoleamine 2,3-dioxygenase 1 (IDO1), the L-tryptophan-degrading enzyme, plays a key role in the immunomodulatory effects on several types of immune cells. Originally known for its regulatory function during pregnancy and chronic inflammation in tumorigenesis, the activity of IDO1 seems to modify the inflammatory state of infectious diseases. The pathophysiologic activity of L-tryptophan metabolites, kynurenines, is well recognized. Therefore, an understanding of the regulation of IDO1 and the subsequent biochemical reactions is essential for the design of therapeutic strategies in certain immune diseases. In this paper, current knowledge about the role of IDO1 and its metabolites during various infectious diseases is presented. Particularly, the regulation of type I interferons (IFNs) production via IDO1 in virus infection is discussed. This paper offers insights into new therapeutic strategies in the modulation of viral infection and several immune-related disorders.

[1]  E. Major,et al.  Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. , 1997, The Biochemical journal.

[2]  A. Hara,et al.  l-Tryptophan–Kynurenine Pathway Metabolites Regulate Type I IFNs of Acute Viral Myocarditis in Mice , 2012, The Journal of Immunology.

[3]  J S Beckman,et al.  Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. , 1996, The American journal of physiology.

[4]  B. Baban,et al.  Leishmania major attenuates host immunity by stimulating local indoleamine 2,3-dioxygenase expression. , 2011, The Journal of infectious diseases.

[5]  P. Guyre,et al.  Inhibition of growth of Toxoplasma gondii in cultured fibroblasts by human recombinant gamma interferon , 1984, Infection and immunity.

[6]  B. Baban,et al.  Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. , 2004, The Journal of clinical investigation.

[7]  G. Solgi,et al.  Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material , 2011, European journal of immunology.

[8]  A. Heitger Regulation of expression and function of IDO in human dendritic cells. , 2011, Current medicinal chemistry.

[9]  B. Baban,et al.  Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. , 2007, The Journal of clinical investigation.

[10]  S. Markey,et al.  Nitration and Inactivation of IDO by Peroxynitrite1 , 2006, The Journal of Immunology.

[11]  C. MacKenzie,et al.  Antimicrobial and immunoregulatory properties of human tryptophan 2,3‐dioxygenase , 2009, European journal of immunology.

[12]  U. Hadding,et al.  Induction of toxoplasmostasis in a human glioblastoma by interferon γ , 1993, Journal of Neuroimmunology.

[13]  E. Major,et al.  Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. , 1992, The Biochemical journal.

[14]  O. Hayaishi,et al.  Tryptophan pyrrolase of rabbit intestine. D- and L-tryptophan-cleaving enzyme or enzymes. , 1967, The Journal of biological chemistry.

[15]  H. Murray,et al.  Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages , 1989, Infection and immunity.

[16]  Osamu Takeuchi,et al.  Innate immunity to virus infection , 2009, Immunological reviews.

[17]  Cory M. Robinson,et al.  The Role of IFN-γ and TNF-α-Responsive Regulatory Elements in the Synergistic Induction of Indoleamine Dioxygenase , 2005 .

[18]  A. Lackner,et al.  Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  B. Veyret,et al.  Murine Macrophages Use Oxygen- and Nitric Oxide-Dependent Mechanisms To Synthesize S-Nitroso-Albumin and To Kill Extracellular Trypanosomes , 1998, Infection and Immunity.

[20]  S. Gupta,et al.  Differential regulation of human indoleamine 2,3-dioxygenase gene expression by interferons-gamma and -alpha. Analysis of the regulatory region of the gene and identification of an interferon-gamma-inducible DNA-binding factor. , 1993, The Journal of biological chemistry.

[21]  H. Yuasa,et al.  Evolution of Vertebrate Indoleamine 2,3-Dioxygenases , 2007, Journal of Molecular Evolution.

[22]  U. Grohmann,et al.  T cell apoptosis by tryptophan catabolism , 2002, Cell Death and Differentiation.

[23]  M. Tymms,et al.  A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Kathy O. Lui,et al.  Infectious tolerance via the consumption of essential amino acids and mTOR signaling , 2009, Proceedings of the National Academy of Sciences.

[25]  N. Nishiyama,et al.  3‐Hydroxykynurenine, an Endogenous Oxidative Stress Generator, Causes Neuronal Cell Death with Apoptotic Features and Region Selectivity , 1998, Journal of neurochemistry.

[26]  C. MacKenzie,et al.  Antimicrobial and immunoregulatory effects mediated by human lung cells: role of IFN-gamma-induced tryptophan degradation. , 2008, FEMS immunology and medical microbiology.

[27]  B. Baban,et al.  GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. , 2005, Immunity.

[28]  J. Korf,et al.  Tryptophan as a Link between Psychopathology and Somatic States , 2003, Psychosomatic medicine.

[29]  Milton W. Taylor,et al.  Relationship between interferon‐γ, indoleamine 2,3‐dioxygenase, and tryptophan catabolism , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  U. Grohmann,et al.  Tryptophan catabolism generates autoimmune-preventive regulatory T cells. , 2006, Transplant immunology.

[31]  U. Grohmann,et al.  Modulation of tryptophan catabolism by regulatory T cells , 2003, Nature Immunology.

[32]  Y. Urade,et al.  Induction of indoleamine 2,3-dioxygenase in mouse lung during virus infection. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[33]  D. Munn,et al.  Inhibition of  T Cell Proliferation by Macrophage Tryptophan Catabolism , 1999, The Journal of experimental medicine.

[34]  M. Takemura,et al.  3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon- γ , 2001, Annals of clinical biochemistry.

[35]  U. Grohmann,et al.  A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice , 2003, The Journal of experimental medicine.

[36]  L. Looger,et al.  Nanosensor Detection of an Immunoregulatory Tryptophan Influx/Kynurenine Efflux Cycle , 2007, PLoS biology.

[37]  B. Hissong,et al.  Potentiation of interferon-induced indoleamine 2,3-dioxygenase mRNA in human mononuclear phagocytes by lipopolysaccharide and interleukin-1. , 1997, Journal of Interferon and Cytokine Research.

[38]  B. Pulendran,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 , 2008, Nature Immunology.

[39]  D. Munn,et al.  Prevention of allogeneic fetal rejection by tryptophan catabolism. , 1998, Science.

[40]  H. Ball,et al.  Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. , 2009, The international journal of biochemistry & cell biology.

[41]  D. Munn,et al.  Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. , 2009, Blood.

[42]  B. Pulendran,et al.  Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI ( 3 ) K-mTOR-p 70 S 6 K pathway , 2022 .

[43]  S. Akira,et al.  Alveolar macrophages are the primary interferon-alpha producer in pulmonary infection with RNA viruses. , 2007, Immunity.

[44]  U. Grohmann,et al.  IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation , 2007, Nature Reviews Immunology.

[45]  G. Prendergast,et al.  Indoleamine 2,3‐dioxygenase in T‐cell tolerance and tumoral immune escape , 2008, Immunological reviews.

[46]  A. Hara,et al.  Inhibition of increased indoleamine 2,3-dioxygenase activity attenuates Toxoplasma gondii replication in the lung during acute infection. , 2012, Cytokine.

[47]  J. McCarter,et al.  Purification and kinetic characterization of human indoleamine 2,3-dioxygenases 1 and 2 (IDO1 and IDO2) and discovery of selective IDO1 inhibitors. , 2011, Biochimica et biophysica acta.

[48]  A. Matsumori,et al.  An Experimental Model for Congestive Heart Failure After Encephalomyocarditis Virus Myocarditis in Mice , 1982, Circulation.

[49]  Milton W. Taylor,et al.  Importance of the Two Interferon-stimulated Response Element (ISRE) Sequences in the Regulation of the Human Indoleamine 2,3-Dioxygenase Gene* , 1996, The Journal of Biological Chemistry.

[50]  A. Luca,et al.  Intranasally delivered siRNA targeting PI3K/Akt/mTOR inflammatory pathways protects from aspergillosis , 2010, Mucosal Immunology.

[51]  G. Damonte,et al.  Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase , 2002, The Journal of experimental medicine.

[52]  M. Gilliet,et al.  Plasmacytoid dendritic cells: key players in the initiation and regulation of immune responses , 2010, Annals of the New York Academy of Sciences.

[53]  A. Thomson,et al.  Tolerogenic plasmacytoid DC , 2010, European journal of immunology.

[54]  U. Grohmann,et al.  Indoleamine 2,3‐dioxygenase: From catalyst to signaling function , 2012, European journal of immunology.

[55]  R. Pine,et al.  Involvement of two regulatory elements in interferon-gamma-regulated expression of human indoleamine 2,3-dioxygenase gene. , 1995, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[56]  M. Schimek,et al.  Vascular Endothelial Expression of Indoleamine 2,3-Dioxygenase 1 Forms a Positive Gradient towards the Feto-Maternal Interface , 2011, PloS one.

[57]  S. Markey,et al.  A mechanism for increased quinolinic acid formation following acute systemic immune stimulation. , 1993, The Journal of biological chemistry.

[58]  Benjamin A Garcia,et al.  Systems-wide proteomic characterization of combinatorial post-translational modification patterns , 2010, Expert review of proteomics.

[59]  U. Grohmann,et al.  CTLA-4, T helper lymphocytes and dendritic cells: an internal perspective of T-cell homeostasis. , 2003, Trends in molecular medicine.

[60]  C. Eyers,et al.  Analysis of post-translational modifications by LC-MS/MS. , 2010, Methods in molecular biology.

[61]  U. Grohmann,et al.  Immunosuppression Via Tryptophan Catabolism: The Role of Kynurenine Pathway Enzymes , 2007, Transplantation.

[62]  R. Radi,et al.  Peroxynitrite-mediated cytotoxicity to Trypanosoma cruzi. , 1993, Archives of biochemistry and biophysics.

[63]  G. Byrne,et al.  Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells , 1986, Infection and immunity.

[64]  H. Morse,et al.  Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice , 1985, The Journal of experimental medicine.

[65]  M. Durcan,et al.  Identification of Tryptophan 2,3‐Dioxygenase RNA in Rodent Brain , 1993, Journal of neurochemistry.

[66]  P. Puccetti,et al.  Toll‐like receptor 9‐mediated induction of the immunosuppressive pathway of tryptophan catabolism , 2006, European journal of immunology.

[67]  A. Cesura,et al.  Expression of the kynurenine enzymes in macrophages and microglial cells: regulation by immune modulators , 2005, Amino Acids.

[68]  A. Aiyar,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 , 2011, Infection and Immunity.

[69]  J S Beckman,et al.  Peroxynitrite formation from macrophage-derived nitric oxide. , 1992, Archives of biochemistry and biophysics.

[70]  O. Hayaishi,et al.  Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. , 1986, The Journal of biological chemistry.

[71]  K. Pardhasaradhi,et al.  Mechanisms of interferon-induced inhibition of Toxoplasma gondii replication in human retinal pigment epithelial cells , 1996, Infection and immunity.

[72]  D. Munn,et al.  Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? , 1999, Immunology today.

[73]  M. Weller,et al.  An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor , 2011, Nature.

[74]  S. Markey,et al.  Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid. , 1992, The Biochemical journal.

[75]  L. Boon,et al.  Cutting Edge: Autocrine TGF-β Sustains Default Tolerogenesis by IDO-Competent Dendritic Cells1 , 2008, The Journal of Immunology.

[76]  Gerhard Opelz,et al.  Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells , 2002, The Journal of experimental medicine.

[77]  G. Trinchieri,et al.  Murine Plasmacytoid Dendritic Cells Initiate the Immunosuppressive Pathway of Tryptophan Catabolism in Response to CD200 Receptor Engagement1 , 2004, The Journal of Immunology.

[78]  R. Radi,et al.  Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. , 1999, Journal of immunology.

[79]  H. Rammensee,et al.  Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? , 2009, Nature Reviews Cancer.

[80]  M. Seishima,et al.  Lipopolysaccharide induction of indoleamine 2,3‐dioxygenase is mediated dominantly by an IFN‐γ‐independent mechanism , 2001, European journal of immunology.

[81]  D. Munn,et al.  Ido expression by dendritic cells: tolerance and tryptophan catabolism , 2004, Nature Reviews Immunology.

[82]  P. Puccetti,et al.  A Crucial Role for Tryptophan Catabolism at the Host/Candida albicans Interface1 , 2005, The Journal of Immunology.

[83]  D. Munn,et al.  Cell‐autonomous control of interferon type I expression by indoleamine 2,3‐dioxygenase in regulatory CD19+ dendritic cells , 2007, European journal of immunology.

[84]  U. Grohmann,et al.  Tolerance, DCs and tryptophan: much ado about IDO. , 2003, Trends in immunology.

[85]  N. Bloksma,et al.  Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model. , 2008, The Journal of allergy and clinical immunology.

[86]  U. Grohmann,et al.  Functional Plasticity of Dendritic Cell Subsets as Mediated by CD40 Versus B7 Activation 1 , 2003, The Journal of Immunology.