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DOI: 10.1160/TH09-04-0250
Antimicrobial and immunoregulatory effector mechanisms in human endothelial cells
Indoleamine 2,3-dioxygenase versus inducible nitric oxide synthase Financial support: This work was supported by the “Deutsche Forschungsgemeinschaft” and the “Ministerium für Bildung und Forschung” to W.D.Publication History
Received:
10 June 2009
Accepted after minor revision:
28 June 2009
Publication Date:
28 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200906/lookinside/thumbnails/10-1160-th09-04-0250-1.jpg)
Summary
In infectious diseases, interferon-gamma (IFN-γ) is generally accepted as one of the most important inducers of antimicrobial and immunoregulatory effects, and both seemingly contradictory effects, can be mediated by the same effector molecules. In detail, several IFN-γ induced enzymes such as the inducible nitric oxide synthase (iNOS) as well as the indoleamine 2,3-dioxygenase (IDO) also exert this double function. In this review we focus on antimicrobial and immunoregulatory properties of both enzymes expressed by human endothelial cells, which are prominent players in infectious diseases, tumour immunology and transplant medicine.
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References
- 1 Griffioen AW, Vyth-Dreese FA. Angiostasis as a way to improve immunotherapy. Thromb Haemost 2009; 101: 1025-1031.
- 2 Dehio C. Bartonella-host-cell interactions and vascular tumour formation. Nat Rev Microbiol 2005; 03: 621-631.
- 3 Walker DH. Rickettsiae and rickettsial infections: the current state of knowledge. Clin Infect Dis 2007; 45 (Suppl. 01) S39-S44.
- 4 Beekhuizen H, van de Gevel JS. Gamma interferon confers resistance to infection with Staphylococcus aureus in human vascular endothelial cells by cooperative proinflammatory and enhanced intrinsic antibacterial activities. Infect Immun 2007; 75: 5615-5626.
- 5 De Assis MC, Da Costa AO, Barja-Fidalgo TC. et al. Human endothelial cells are activated by interferongamma plus tumour necrosis factor-alpha to kill intracellular Pseudomonas aeruginosa . Immunology 2000; 101: 271-278.
- 6 Hunt NH, Golenser J, Chan-Ling T. et al. Immunopathogenesis of cerebral malaria. Int J Parasitol 2006; 36: 569-582.
- 7 Grubb SE, Murdoch C, Sudbery PE. et al. Candida albicans-endothelial cell interactions: a key step in the pathogenesis of systemic candidiasis. Infect Immun 2008; 76: 4370-4377.
- 8 Müthing J, Schweppe CH, Karch H. et al. Shiga toxins, glycosphingolipid diversity, and endothelial cell injury. Thromb Haemost 2009; 101: 252-264.
- 9 Jong A, Wu CH, Zhou W. et al. Infectomic analysis of gene expression profiles of human brain microvascular endothelial cells infected with Cryptococcus neoformans . J Biomed Biotechnol 2008; 2008: 375620.
- 10 Bolovan-Fritts CA, Trout RN, Spector SA. Human cytomegalovirus-specific CD4+-T-cell cytokine response induces fractalkine in endothelial cells. J Virol 2004; 78: 13173-13181.
- 11 Däubener W, Spors B, Hucke C. et al. Restriction of Toxoplasma gondii growth in human brain microvascular endothelial cells by activation of indoleamine 2,3-dioxygenase. Infect Immun 2001; 69: 6527-6531.
- 12 Schroten H, Spors B, Hucke C. et al. Potential role of human brain microvascular endothelial cells in the pathogenesis of brain abscess: inhibition of Staphylococcus aureus by activation of indoleamine 2,3-dioxygenase. Neuropediatrics 2001; 32: 206-210.
- 13 Woods ME, Olano JP. Host defenses to Rickettsia rickettsii infection contribute to increased microvascular permeability in human cerebral endothelial cells. J Clin Immunol 2008; 28: 174-185.
- 14 Adam R, Rüssing D, Adams O. et al. Role of human brain microvascular endothelial cells during central nervous system infection. Significance of indoleamine 2,3-dioxygenase in antimicrobial defence and immunoregulation. Thromb Haemost 2005; 94: 341-346.
- 15 MacKenzie CR, Heseler K, Müller A. et al. Role of indoleamine 2,3-dioxygenase in antimicrobial defence and immuno-regulation: tryptophan depletion versus production of toxic kynurenines. Curr Drug Metab 2007; 08: 237-244.
- 16 Chi JT, Chang HY, Haraldsen G. et al. Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci U S A 2003; 100: 10623-10628.
- 17 Bogdan C, Rollinghoff M, Diefenbach A. Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr Opin Immunol 2000; 12: 64-76.
- 18 Kroll J, Waltenberger J. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun 1998; 252: 743-746.
- 19 Assis MC, Freitas C, Saliba AM. et al. Up-regulation of Fas expression by Pseudomonas aeruginosainfected endothelial cells depends on modulation of iNOS and enhanced production of NO induced by bacterial type III secreted proteins. Int J Mol Med 2006; 18: 355-363.
- 20 Pino P, Vouldoukis I, Kolb JP. et al. Plasmodium falciparum-infected erythrocyte adhesion induces caspase activation and apoptosis in human endothelial cells. J Infect Dis 2003; 187: 1283-1290.
- 21 Gomez RM, Pozner RG, Lazzari MA. et al. Endothelial cell function alteration after Junin virus infection. Thromb Haemost 2003; 90: 326-333.
- 22 Matejovic M, Krouzecky A, Radej J. Coagulation and endothelial dysfunction during long-term hyperdynamic porcine bacteremia-effects of selective inducible nitric oxide synthase inhibition. Thromb Haemost 2007; 97: 304-309.
- 23 Rosenkranz-Weiss P, Sessa WC, Milstien S. et al. Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J Clin Invest 1994; 93: 2236-2243.
- 24 Feng HM, Walker DH. Mechanisms of intracellular killing of Rickettsia conorii in infected human endothelial cells, hepatocytes, and macrophages. Infect Immun 2000; 68: 6729-6736.
- 25 Orpana A, Ranta V, Mikkola T. et al. Inducible nitric oxide and prostacyclin productions are differently controlled by extracellular matrix and cell density in human vascular endothelial cells. J Cell Biochem 1997; 64: 538-546.
- 26 Däubener W, Nockemann S, Gutsche M. et al. Heparin inhibits the antiparasitic and immune modulatory effects of human recombinant interferon-gamma. Eur J Immunol 1995; 25: 688-692.
- 27 Däubener W, Gutsche M, Nockemann S. et al. Protamine enhances the activity of human recombinant interferon-gamma. J Interferon Cytokine Res 1996; 16: 531-536.
- 28 Pfefferkorn ER. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc Natl Acad Sci U S A 1984; 81: 908-912.
- 29 Munn DH, Zhou M, Attwood JT. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998; 281: 1191-1193.
- 30 Maghzal GJ, Thomas SR, Hunt NH. et al. Cytochrome b5, not superoxide anion radical, is a major reductant of indoleamine 2,3-dioxygenase in human cells. J Biol Chem 2008; 283: 12014-12025.
- 31 Shashar N, Harosi FI, Banaszak AT. et al. UV radiation blocking compounds in the eye of the cuttlefish Sepia officinalis . Biol Bull 1998; 195: 187-188.
- 32 Takikawa O, Littlejohn TK, Truscott RJ. Indoleamine 2,3-dioxygenase in the human lens, the first enzyme in the synthesis of UV filters. Exp Eye Res 2001; 72: 271-277.
- 33 Serbecic N, Beutelspacher SC. Indoleamine 2,3-dioxygenase protects corneal endothelial cells from UV mediated damage. Exp Eye Res 2006; 82: 416-426.
- 34 Adam RA, Tenenbaum T, Valentin-Weigand P. et al. Porcine choroid plexus epithelial cells induce Streptococcus suis bacteriostasis in vitro . Infect Immun 2004; 72: 3084-3087.
- 35 MacKenzie CR, Hadding U, Däubener W. Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. J Infect Dis 1998; 178: 875-878.
- 36 MacKenzie CR, Hucke C, Müller D. et al. Growth inhibition of multiresistant enterococci by interferongamma-activated human uro-epithelial cells. J Med Microbiol 1999; 48: 935-941.
- 37 Byrne GI, Lehmann LK, Landry GJ. Induction of tryptophan catabolism is the mechanism for gammainterferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells. Infect Immun 1986; 53: 347-351.
- 38 Beutelspacher SC, Tan PH, McClure MO. et al. Expression of indoleamine 2,3-dioxygenase (IDO) by endothelial cells: implications for the control of alloresponses. Am J Transplant 2006; 06: 1320-1330.
- 39 Müller A, Heseler K, Schmidt SK. et al. The missing link between Indoleamine 2,3-dioxygenase mediated antimicrobial and immunoregulatory effects. J Cell Mol Med 2009; 06: 1125-1135.
- 40 Hansen AM, Ball HJ, Mitchell AJ. et al. Increased expression of indoleamine 2,3-dioxygenase in murine malaria infection is predominantly localised to the vascular endothelium. Int J Parasitol 2004; 34: 1309-1319.
- 41 Woodman JP, Dimier IH, Bout DT. Human endothelial cells are activated by IFN-gamma to inhibit Toxoplasma gondii replication. Inhibition is due to a different mechanism from that existing in mouse macrophages and human fibroblasts. J Immunol 1991; 147: 2019-2023.
- 42 Terajima M, Leporati AM. Role of indoleamine 2,3-dioxygenase in antiviral activity of interferongamma against vaccinia virus. Viral Immunol 2005; 18: 722-729.
- 43 Obojes K, Andres O, Kim KS. et al. Indoleamine 2,3-dioxygenase mediates cell type-specific antimeasles virus activity of gamma interferon. J Virol 2005; 79: 7768-7776.
- 44 Bodaghi B, Goureau O, Zipeto D. et al. Role of IFN-gamma-induced indoleamine 2,3 dioxygenase and inducible nitric oxide synthase in the replication of human cytomegalovirus in retinal pigment epithelial cells. J Immunol 1999; 162: 957-964.
- 45 Adams O, Besken K, Oberdörfer C. et al. Role of indoleamine-2,3-dioxygenase in alpha/beta and gamma interferon-mediated antiviral effects against herpes simplex virus infections. J Virol 2004; 78: 2632-2636.
- 46 Adams O, Besken K, Oberdörfer C. et al. Inhibition of human herpes simplex virus type 2 by interferon gamma and tumor necrosis factor alpha is mediated by indoleamine 2,3-dioxygenase. Microbes Infect 2004; 06: 806-812.
- 47 Miller DM, Rahill BM, Boss JM. et al. Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. J Exp Med 1998; 187: 675-683.
- 48 Honig A, Rieger L, Kapp M. et al. Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance. J Reprod Immunol 2004; 61: 79-86.
- 49 Ligam P, Manuelpillai U, Wallace EM. et al. Localisation of indoleamine 2,3-dioxygenase and kynurenine hydroxylase in the human placenta and decidua: implications for role of the kynurenine pathway in pregnancy. Placenta 2005; 26: 498-404.
- 50 Drenzek JG, Breburda EE, Burleigh DW. et al. Expression of indoleamine 2,3-dioxygenase in the rhesus monkey and common marmoset. J Reprod Immunol 2008; 78: 125-133.
- 51 Kwidzinski E, Bunse J, Aktas O. et al. Indolamine 2,3-dioxygenase is expressed in the CNS and downregulates autoimmune inflammation. FASEB J 2005; 19: 1347-1349.
- 52 Sakurai K, Zou JP, Tschetter Ward JR. et al. Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis. J Neuroimmunol 2002; 129: 186-196.
- 53 Grohmann U, Fallarino F, Bianchi R. et al. A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice. J Exp Med 2003; 198: 153-160.
- 54 Ozaki Y, Edelstein MP, Duch DS. Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. Proc Natl Acad Sci U S A 1988; 85: 1242-1246.
- 55 Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 2007; 117: 1147-1154.
- 56 Uyttenhove C, Pilotte L, Theate I. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003; 09: 1269-1274.
- 57 Munn DH, Sharma MD, Hou D. et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 2004; 114: 280-290.
- 58 Feder-Mengus C, Wyler S, Hudolin T. et al. High expression of indoleamine 2,3-dioxygenase gene in prostate cancer. Eur J Cancer 2008; 44: 2266-2275.
- 59 Riesenberg R, Weiler C, Spring O. et al. Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma. Clin Cancer Res 2007; 13: 6993-6902.
- 60 Ma W, Pober JS. Human endothelial cells effectively costimulate cytokine production by, but not differentiation of, naive CD4+ T cells. J Immunol 1998; 161: 2158-2167.
- 61 McDouall RM, Page CS, Hafizi S. et al. Alloproliferation of purified CD4+ T cells to adult human heart endothelial cells, and study of second-signal requirements. Immunology 1996; 89: 220-226.
- 62 Beutelspacher SC, Pillai R, Watson MP. et al. Function of indoleamine 2,3-dioxygenase in corneal allograft rejection and prolongation of allograft survival by over-expression. Eur J Immunol 2006; 36: 690-700.
- 63 Liu H, Liu L, Fletcher BS. et al. Novel action of indoleamine 2,3-dioxygenase attenuating acute lung allograft injury. Am J Respir Crit Care Med 2006; 173: 566-572.
- 64 Liu H, Liu L, Visner GA. Nonviral gene delivery with indoleamine 2,3-dioxygenase targeting pulmonary endothelium protects against ischemia-reperfusion injury. Am J Transplant 2007; 07: 2291-2300.