Abstract
Metabolism of the essential amino acid tryptophan (trp) is a key endogenous immunosuppressive pathway restricting inflammatory responses. Tryptophan metabolites promote regulatory T cell (Treg) differentiation and suppress proinflammatory T helper cell (Th)1 and Th17 phenotypes. It has been shown that treatment with natural and synthetic tryptophan metabolites can suppress autoimmune neuroinflammation in preclinical animal models. Here, we tested if oral intake of tryptophan would increase immunosuppressive tryptophan metabolites and ameliorate autoimmune neuroinflammation as a safe approach to treat autoimmune disorders like multiple sclerosis (MS). Without oral supplementation, systemic kynurenine levels decrease during the initiation phase of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, indicating systemic activation of tryptophan metabolism. Daily oral gavage of up to 10 mg/mouse/day was safe and increased serum kynurenine levels by more than 20-fold for more than 3 h after the gavage. While this treatment resulted in suppression of myelin-specific Th1 responses, there was no relevant impact on clinical disease activity. These data show that oral trp supplementation at subtoxic concentrations suppresses antigen-specific Th1 responses, but suggest that the increase in trp metabolites is not sustained enough to impact neuroinflammation.
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References
Brooks AK, Lawson MA, Smith RA et al (2016) Interactions between inflammatory mediators and corticosteroids regulate transcription of genes within the Kynurenine Pathway in the mouse hippocampus. J Neuroinflammation 13:98. doi:10.1186/s12974-016-0563-1
Campesan S, Green EW, Breda C et al (2011) The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Curr Biol 21:961–966. doi:10.1016/j.cub.2011.04.028
Fallarino F, Vacca C, Orabona C et al (2002) Functional expression of indoleamine 2,3-dioxygenase by murine CD8 alpha(+) dendritic cells. Int Immunol 14:65–68
FDA (2005) Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Pharmacol Toxicol 1–27
Forrest CM, Mackay GM, Stoy N et al (2004) Tryptophan loading induces oxidative stress. Free Radic Res 38:1167–1171. doi:10.1080/10715760400011437
George CF, Millar TW, Hanly PJ, Kryger MH (1989) The effect of l-tryptophan on daytime sleep latency in normals: correlation with blood levels. Sleep 12:345–353
Glassman AH, Platman SR (1969) Potentiation of a monoamine oxidase inhibitor by tryptophan. J Psychiatr Res 7:83–88
Gullino P, Winitz M, Birnbaum SM et al (1956) Studies on the metabolism of amino acids and related compounds in vivo. I. Toxicity of essential amino acids, individually and in mixtures, and the protective effect of l-arginine. Arch Biochem Biophys 64:319–332
Herrington RN, Bruce A, Johnstone EC (1974) Comparative trial of l-tryptophan and E.C.T. in severe depressive illness. Lancet 2:731–734
Heuther G, Hajak G, Reimer A et al (1992) The metabolic fate of infused l-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites. Psychopharmacology 109:422–432
Hyyppä MT, Falck SC (1977) l-tryptophan and neuroendocrine regulation in neurologic patients: gonadotrophin secretion, sexual motivation and responsiveness during l-tryptophan treatment in patients with multiple sclerosis (MS). Psychoneuroendocrinology 2:359–363
Inglis JJ, Criado G, Andrews M et al (2007) The anti-allergic drug, N-(3“,4-”dimethoxycinnamonyl) anthranilic acid, exhibits potent anti-inflammatory and analgesic properties in arthritis. Rheumatology 46:1428–1432. doi:10.1093/rheumatology/kem160
Jäger A, Dardalhon V, Sobel RA et al (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183:7169–7177. doi:10.4049/jimmunol.0901906
Keil M, Sonner JK, Lanz TV et al (2016) General control non-derepressible 2 (GCN2) in T cells controls disease progression of autoimmune neuroinflammation. J Neuroimmunol 297:117–126. doi:10.1016/j.jneuroim.2016.05.014
Kwidzinski E, Bunse J, Aktas O et al (2005) Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J 19:1347–1349. doi:10.1096/fj.04-3228fje
Lanz TV, Williams SK, Stojic A et al (2017) Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis. Sci Rep 7:41271. doi:10.1038/srep41271
Metz R, Rust S, DuHadaway JB et al (2012) IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by d-1-methyl-tryptophan. Oncoimmunology 1:1460–1468. doi:10.4161/onci.21716
Mezrich JD, Fechner JH, Zhang X et al (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185:3190–3198. doi:10.4049/jimmunol.0903670
Michael AF, Drummond KN, Doeden D et al (1964) Tryptophan metabolism in man. J Clin Invest 43:1730–1746. doi:10.1172/JCI105048
Muller AJ, Sharma MD, Chandler PR et al (2008) Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc Natl Acad Sci USA 105:17073–17078. doi:10.1073/pnas.0806173105
Munn DH, Zhou M, Attwood JT et al (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193
Munn DH, Sharma MD, Baban B et al (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22:633–642. doi:10.1016/j.immuni.2005.03.013
Nguyen NT, Kimura A, Nakahama T et al (2010) Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA 107:19961–19966. doi:10.1073/pnas.1014465107
Obrenovitch TP, Urenjak J (2000) In vivo assessment of kynurenate neuroprotective potency and quinolinate excitotoxicity. Amino Acids 19:299–309
Ohira K, Hagihara H, Toyama K et al (2010) Expression of tryptophan 2,3-dioxygenase in mature granule cells of the adult mouse dentate gyrus. Mol Brain 3:26. doi:10.1186/1756-6606-3-26
Opitz CA, Wick W, Steinman L, Platten M (2007) Tryptophan degradation in autoimmune diseases. Cell Mol Life Sci 64:2542–2563. doi:10.1007/s00018-007-7140-9
Opitz CA, Litzenburger UM, Sahm F et al (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203. doi:10.1038/nature10491
Orsini H, Araujo LP, Maricato JT et al (2014) GCN2 kinase plays an important role triggering the remission phase of experimental autoimmune encephalomyelitis (EAE) in mice. Brain Behav Immun 37:177–186. doi:10.1016/j.bbi.2013.12.012
Pilotte L, Larrieu P, Stroobant V et al (2012) Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci USA 109:2497–2502. doi:10.1073/pnas.1113873109
Platten M, Ho PP, Youssef S et al (2005) Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science 310:850–855. doi:10.1126/science.1117634
Platten M, Wick W, Van den Eynde BJ (2012) Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res 72:5435–5440. doi:10.1158/0008-5472.CAN-12-0569
Quintana FJ, Basso AS, Iglesias AH et al (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71. doi:10.1038/nature06880
Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661. doi:10.1096/fj.07-9574LSF
Sainio EL, Sainio P (1990) Comparison of effects of nicotinic acid or tryptophan on tryptophan 2,3-dioxygenase in acute and chronic studies. Toxicol Appl Pharmacol 102:251–258
Sakurai K, Zou J-P, Tschetter JR et al (2002) Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis. J Neuroimmunol 129:186–196
Sandyk R (1992) L-tryptophan in neuropsychiatric disorders: a review. Int J Neurosci 67:127–144
Terness P, Bauer TM, Röse L et al (2002) Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196:447–457. doi:10.1084/jem.20020052
Urenjak J, Obrenovitch TP (2000) Neuroprotective potency of kynurenic acid against excitotoxicity. NeuroReport 11:1341–1344
Veldhoen M, Hirota K, Westendorf AM et al (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109. doi:10.1038/nature06881
Walker AK, Budac DP, Bisulco S et al (2013) NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology 38:1609–1616. doi:10.1038/npp.2013.71
Yan Y, Zhang G-X, Gran B et al (2010) IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185:5953–5961. doi:10.4049/jimmunol.1001628
Young SN, St-Arnaud-McKenzie D, Sourkes TL (1978) Importance of tryptophan pyrrolase and aromatic amino acid decarboxylase in the catabolism of tryptophan. Biochem Pharmacol 27:763–767
Acknowledgements
This work was supported by the German Research Foundation (DFG, SFB938, TPK, FOR2289, P8, Z1) to MP and WW, the German Cancer Aid (Deutsche Krebshilfe, 110392) to MP, the Helmholtz Association (Helmholtz-Gesellschaft) to MP, the Heidelberg University Innovation Fund FRONTIER to MP, the Hertie Foundation (Hertie-Stiftung) to WW and the Postdoc Fellowship Program of the Medical Faculty of the University of Heidelberg to TVL.
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All applicable international, national, and institutional guidelines for the care and use of animals were followed under the permission of the “Regierungspräsidium” in Karlsruhe, Germany, and the “Tierlaborausschuss” of the German Cancer Research Center (DKFZ) in Heidelberg, Germany. This article does not contain any studies with human participants performed by any of the authors.
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Lanz, T.V., Becker, S., Mohapatra, S.R. et al. Suppression of Th1 differentiation by tryptophan supplementation in vivo. Amino Acids 49, 1169–1175 (2017). https://doi.org/10.1007/s00726-017-2415-4
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DOI: https://doi.org/10.1007/s00726-017-2415-4