Abstract
Chronic immune activation is encountered in different pathologies including granulomatous and functional bowel diseases, cancer, aging, atherosclerosis, and obesity. Persistence of chronic inflammatory stimuli over time creates a biologic background for immunosenescence and favors neopterin formation with the enhanced tryptophan (Trp) degradation in diseases concomitant with cellular immune activation. Trp degradation leads to the generation of several neuroactive compounds by three distinct pathways.
Indoleamine 2,3-dioxygenase (IDO) induction leads to many complex changes within the affected cells resulting in immunosuppression through breakdown of Trp. Thus, neopterin concentrations as well as IDO expression significantly increase in inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease.
However, irritable bowel syndrome (IBS) is linked with abnormal serotonin functioning and immune activation. In this case, enteric serotonin (5-HT) signaling may be defective and inactivated by the serotonin-selective reuptake transporter (SERT) in the enterocytes. A positive correlation is evident between IBS severity and kynurenine (Kyn) to Trp ratio which is significantly correlated with the rise of interferon (IFN)-gamma.
The dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. IDO-reactive T cells are able to recognize and kill tumor cells as well as IDO-expressing dendritic cells (DCs). IDO activation leads to immunosuppression through breakdown of Trp in the tumor microenvironment and tumor-draining lymph nodes. C-C chemokine receptor type 4 (CCR4)+ forkhead boxp3(Foxp3)+ regulatory T (Treg) cells create a favorable environment for tumor escape from host immune responses. Thus, Foxp3+/IDO+ tumors are associated with more advanced disease.
Age-related changes in the immune system are known as immunosenescence. A causal relationship is evident between the Trp metabolism and immune deficiency in elderly. Eventually, the reduced serum Trp concentrations and increased Kyn levels indicate increased chronic low-grade inflammation in elderly. In this case, IDO-induced Trp degradation is associated with increase in neopterin and nitrite levels. The amounts of neopterin produced by activated macrophages correlate with their capacity to release reactive oxygen species (ROS). Melatonin not only improves the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes but also reduces free radical generation. The decline in melatonin production in aged individuals is a primary contributing factor for the development of age-associated neuronal damage.
IDO activity also has a significant positive correlation in both sexes with carotid artery intima/media thickness as an early marker of atherosclerosis. Enhanced Trp degradation in patients with coronary heart disease correlates with enhanced neopterin formation. In addition to elevated Kyn to Trp ratio, neopterin concentrations correlate with the abdominal obesity and metabolic syndrome.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Avanzas P, Arroyo-Espliguero R, Cosin-Sales J, Quiles J, Zouridakis E, Kaski JC (2004) Prognostic value of neopterin levels in treated patients with hypertension and chest pain but without obstructive coronary artery disease. Am J Cardiol 93:627–629
Avanzas P, Arroyo-Espliguero R, Quiles J, Roy D, Kaski JC (2005) Elevated serum neopterin predicts future adverse cardiac events in patients with chronic stable angina pectoris. Eur Heart J 26:457–463
Bassal NK, Hughes BP, Costabile M (2012) Arachidonic acid and its COX1/2 metabolites inhibit interferon-γ mediated induction of indoleamine-2,3 dioxygenase in THP-1 cells and human monocytes. Prostaglandins Leukot Essent Fat Acids 87:119–126
Becker K, Schroecksnadel S, Gostner J, Zaknun C, Schennach H, Uberall F, Fuchs D (2014) Comparison of in vitro tests for antioxidant and immunomodulatory capacities of compounds. Phytomedicine 21:164–171
Bell C, Abrams J, Nutt D (2001) Tryptophan depletion and its implications for psychiatry. Br J Psychiatry 178:399–405
Belmonte L, Beutheu Youmba S, Bertiaux-Vandaële N, Antonietti M, Lecleire S, Zalar A, Gourcerol G, Leroi AM, Déchelotte P, Coëffier M, Ducrotté P (2012) Role of toll like receptors in irritable bowel syndrome: differential mucosal immune activation according to the disease subtype. PLoS One 7:e42777
Blasi C (2008) The autoimmune origin of atherosclerosis. Atherosclerosis 201:17–32
Braidy N, Grant R, Brew BJ, Adams S, Jayasena T, Guillemin GJ (2009) Effects of kynurenine pathway metabolites on intracellular NAD synthesis and cell death in human primary astrocytes and neurons. Int J Tryptophan Res 2:61–69
Brandacher G, Winkler C, Aigner F, Schwelberger H, Schroecksnadel K, Margreiter R, Fuchs D, Weiss HG (2006) Bariatric surgery cannot prevent tryptophan depletion due to chronic immune activation in morbidly obese patients. Obes Surg 16:541–548
Brandacher G, Hoeller E, Fuchs D, Weiss HG (2007) Chronic immune activation underlies morbid obesity: is IDO a key player? Curr Drug Metab 8:289–295
Brenk M, Scheler M, Koch S, Neumann J, Takikawa O, Häcker G, Bieber T, von Bubnoff D (2009) Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. J Immunol 183:145–154
Brewer JW, Hendershot LM, Sherr CJ, Diehl JA (1999) Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression. Proc Natl Acad Sci U S A 96:8505–8510
Burke SJ, Updegraff BL, Bellich RM, Goff MR, Lu D, Minkin SC Jr, Karlstad MD, Collier JJ (2013) Regulation of iNOS gene transcription by IL-1β and IFN-γ requires a coactivator exchange mechanism. Mol Endocrinol 27:1724–1742
Candore G, Colonna-Romano G, Balistreri CR, Di Carlo D, Grimaldi MP, Listì F, Nuzzo D, Vasto S, Lio D, Caruso C (2006) Biology of longevity: role of the innate immune system. Rejuvenation Res 9:143–148
Capuron L, Schroecksnadel S, Féart C, Aubert A, Higueret D, Barberger-Gateau P, Layé S, Fuchs D (2011) Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. Biol Psychiatry 70:175–182
Chen Y, Guillemin GJ (2009) Kynurenine pathway metabolites in humans: disease and healthy States. Int J Tryptophan Res 2:1–19
Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR (2008) The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol 181:5396–5404
Chen CQ, Fichna J, Bashashati M, Li YY, Storr M (2011) Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol 17:3888–3898
Clarke G, Fitzgerald P, Cryan JF, Cassidy EM, Quigley EM, Dinan TG (2009) Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort. BMC Gastroenterol 9:6
Clarke G, McKernan DP, Gaszner G, Quigley EM, Cryan JF, Dinan TG (2012) A distinct profile of tryptophan metabolism along the kynurenine pathway downstream of toll-like receptor activation in irritable bowel syndrome. Front Pharmacol 3:90
Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, Crowell MD, Sharkey KA, Gershon MD, Mawe GM, Moses PL (2004) Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 126:1657–1664
Colucci R, Blandizzi C, Bellini M, Ghisu N, Tonini M, Del Tacca M (2008) The genetics of the serotonin transporter and irritable bowel syndrome. Trends Mol Med 14:295–304
Coon SL, Del Olmo E, Young WS 3rd, Klein DC (2002) Melatonin synthesis enzymes in Macaca mulatta: focus on arylalkylamine N-acetyltransferase (EC 2.3.1.87). J Clin Endocrinol Metab 87:4699–4706
Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16:90–97
Cremon C, Gargano L, Morselli-Labate AM, Santini D, Cogliandro RF, De Giorgio R, Stanghellini V, Corinaldesi R, Barbara G (2009) Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol 104:392–400
Crowell MD, Wessinger SB (2007) 5-HT and the brain-gut axis: opportunities for pharmacologic intervention. Expert Opin Investig Drugs 16:761–765
D’Angelo JA, Dehlink E, Platzer B, Dwyer P, Circu ML, Garay J, Aw TY, Fiebiger E, Dickinson BL (2010) The cystine/glutamate antiporter regulates dendritic cell differentiation and antigen presentation. J Immunol 185:3217–3226
Dalgleish AG, O’Byrne KJ (2002) Chronic immune activation and inflammation in the pathogenesis of aids and cancer. Adv Cancer Res 84:231–276
Danese S (2011) Role of the vascular and lymphatic endothelium in the pathogenesis of inflammatory bowel disease: ‘brothers in arms’. Gut 60:998–1008
Danese S, Fiocchi C (2006) Etiopathogenesis of inflammatory bowel diseases. World J Gastroenterol 12:4807–4812
De Haro C, Méndez R, Santoyo J (1996) The eIF-2alpha kinases and the control of protein synthesis. FASEB J 10:1378–1387
Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J (2010) International union of basic and clinical pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev 62:343–380
Duncan BB, Schmidt MI (2001) Chronic activation of the innate immune system may underlie the metabolic syndrome. Sao Paulo Med J 119:122–127
El Assar M, Angulo J, Rodríguez-Mañas L (2013) Oxidative stress and vascular inflammation in aging. Free Radic Biol Med 65C:380–401
El-Salhy M, Wendelbo I, Gundersen D (2013) Serotonin and serotonin transporter in the rectum of patients with irritable bowel disease. Mol Med Rep 8:451–455
Engin AB, Engin A, Gonul II, Karamercan A, Sepici-Dincel A, Dursun A (2010) Tumor invasion pattern and related serum tryptophan and neopterin concentrations in colorectal carcinomas. Pteridines 16:35
Fallarino F, Grohmann U, Vacca C, Orabona C, Spreca A, Fioretti MC, Puccetti P (2003) T cell apoptosis by kynurenines. Adv Exp Med Biol 527:183–190
Feksa LR, Latini A, Rech VC, Wajner M, Dutra-Filho CS, de Souza Wyse AT, Wannmacher CM (2006) Promotion of oxidative stress by L-tryptophan in cerebral cortex of rats. Neurochem Int 49:87–93
Feksa LR, Latini A, Rech VC, Feksa PB, Koch GD, Amaral MF, Leipnitz G, Dutra-Filho CS, Wajner M, Wannmacher CM (2008) Tryptophan administration induces oxidative stress in brain cortex of rats. Metab Brain Dis 23:221–233
Fitzgerald P, Cassidy Eugene M, Clarke G, Scully P, Barry S, Quigley Eamonn MM, Shanahan F, Cryan J, Dinan TG (2008) Tryptophan catabolism in females with irritable bowel syndrome: relationship to interferon-gamma, severity of symptoms and psychiatric co-morbidity. Neurogastroenterol Motil 20:1291–1297
Forouzandeh F, Jalili RB, Germain M, Duronio V, Ghahary A (2008) Differential immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO) on primary human CD4+ and CD8+ T cells. Mol Cell Biochem 309:1–7
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254
Frazão JB, Errante PR, Condino-Neto A (2013) Toll-like receptors’ pathway disturbances are associated with increased susceptibility to infections in humans. Arch Immunol Ther Exp (Warsz) 61:427–443
Frick B, Schroecksnadel K, Neurauter G, Leblhuber F, Fuchs D (2004) Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clin Biochem 37:684–687
Fuchs D, Avanzas P, Arroyo-Espliguero R, Jenny M, Consuegra-Sanchez L, Kaski JC (2009) The role of neopterin in atherogenesis and cardiovascular risk assessment. Curr Med Chem 16:4644–4653
Fukudo S (2013) Stress and visceral pain: focusing on irritable bowel syndrome. Pain 154(Suppl 1):S63–S70
García-Lestón J, Roma-Torres J, Mayan O, Schroecksnadel S, Fuchs D, Moreira AO, Pásaro E, Méndez J, Teixeira JP, Laffon B (2012) Assessment of immunotoxicity parameters in individuals occupationally exposed to lead. J Toxicol Environ Health A 75:807–818
Gershon MD (2004) Review article: serotonin receptors and transporters: roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther 20(Suppl 7):3–14
Gershon MD, Tack J (2007) The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132:397–414
Ghosh D, Levault KR, Brewer GJ (2014) Dual-energy precursor and nuclear erythroid-related factor 2 activator treatment additively improve redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of reactive oxygen species. Neurobiol Aging 35:179–190
Grammer TB, Fuchs D, Boehm BO, Winkelmann BR, Maerz W (2009) Neopterin as a predictor of total and cardiovascular mortality in individuals undergoing angiography in the Ludwigshafen risk and cardiovascular health study. Clin Chem 55:1135–1146
Gross B, Ronen N, Reznick A, Mokady S, Honigman S, Livne E (1996) Biochemical and morphological changes observed in rat muscles following consumption of excessive 1-tryptophan and atherogenic diets. Adv Exp Med Biol 398:575–578
Gross B, Ronen N, Honigman S, Livne E (1999) Tryptophan toxicity – time and dose response in rats. Adv Exp Med Biol 467:507–516
Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA (2005) PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell 16:5493–5501
Hannon J, Hoyer D (2008) Molecular biology of 5-HT receptors. Behav Brain Res 195:198–213
Hausmann M, Kiessling S, Mestermann S, Webb G, Spöttl T, Andus T, Schölmerich J, Herfarth H, Ray K, Falk W, Rogler G (2002) Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. Gastroenterology 122:1987–2000
Hayashi T, Mo JH, Gong X, Rossetto C, Jang A, Beck L, Elliott GI, Kufareva I, Abagyan R, Broide DH, Lee J, Raz E (2007) 3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis. Proc Natl Acad Sci U S A 104:18619–18624
Heiss EH, Schachner D, Werner ER, Dirsch VM (2009) Active NF-E2-related factor (Nrf2) contributes to keep endothelial NO synthase (eNOS) in the coupled state: role of reactive oxygen species (ROS), eNOS, and heme oxygenase (HO-1) levels. J Biol Chem 284:31579–31586
Herpfer I, Greilberger J, Ledinski G, Widner B, Fuchs D, Jurgens G (2002) Neopterin and 7,8-dihydroneopterin interfere with low density lipoprotein oxidation mediated by peroxynitrite and/or copper. Free Radic Res 36:509–520
Hoffmann G, Wirleitner B, Fuchs D (2003) Potential role of immune system activation-associated production of neopterin derivatives in humans. Inflamm Res 52:313–321
Hosseini-Tabatabaei A, Jalili RB, Li Y, Kilani RT, Moeen Rezakhanlou A, Ghahary A (2012) Mechanism underlying defective interferon gamma-induced IDO expression in non-obese diabetic mouse fibroblasts. PLoS One 7(5):e37747
Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554
Huang A, Zhang Y, Chen K, Hatakeyama K, Keaney JF Jr (2005) Cytokine-stimulated GTP cyclohydrolase I expression in endothelial cells requires coordinated activation of nuclear factor-kappaB and Stat1/Stat3. Circ Res 96:164–171
Husain N, Tokoro K, Popov JM, Naides SJ, Kwasny MJ, Buchman AL (2013) Neopterin concentration as an index of disease activity in Crohn’s disease and ulcerative colitis. J Clin Gastroenterol 47:246–251
Ichinose H, Homma D, Sumi-Ichinose C, Nomura T, Kondo K (2013) GTP cyclohydrolase regulation: implications for brain development and function. Adv Pharmacol 68:23–35
Ishida T, Ueda R (2006) CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci 97:1139–1146
Iuvone PM, Tosini G, Pozdeyev N, Haque R, Klein DC, Chaurasia SS (2005) Circadian clocks, clock networks, arylalkylamine N-acetyltransferase, and melatonin in the retina. Prog Retin Eye Res 24:433–456
Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825
Keszthelyi D, Troost FJ, Jonkers DM, van Donkelaar EL, Dekker J, Buurman WA, Masclee AA (2012) Does acute tryptophan depletion affect peripheral serotonin metabolism in the intestine? Am J Clin Nutr 95:603–608
Klein DC (2007) Arylalkylamine N-acetyltransferase: “the timezyme”. J Biol Chem 282:4233–4237
Krogsgaard LR, Engsbro AL, Bytzer P (2013) The epidemiology of irritable bowel syndrome in Denmark. A population-based survey in adults ≤50 years of age. Scand J Gastroenterol 48:523–529
Lázaro I, Ferré R, Masana L, Cabré A (2013) Akt and ERK/Nrf2 activation by PUFA oxidation-derived aldehydes upregulates FABP4 expression in human macrophages. Atherosclerosis 230:216–222
Li N, McLaren JE, Michael DR, Clement M, Fielding CA, Ramji DP (2010) ERK is integral to the IFN-γ-mediated activation of STAT1, the expression of key genes implicated in atherosclerosis, and the uptake of modified lipoproteins by human macrophages. J Immunol 185:3041–3048
Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701–1711
Mangge H, Summers KL, Meinitzer A, Zelzer S, Almer G, Prassl R, Schnedl WJ, Reininghaus E, Paulmichl K, Weghuber D, Fuchs D (2014) Obesity-related dysregulation of the Tryptophan-Kynurenine metabolism: role of age and parameters of the metabolic syndrome. Obesity (Silver Spring) 22:195–201
Mansfield AS, Heikkila PS, Vaara AT, von Smitten KA, Vakkila JM, Leidenius MH (2009) Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast. BMC Cancer 9:231
Martel F (2006) Recent advances on the importance of the serotonin transporter SERT in the rat intestine. Pharmacol Res 54:73–76
Mattox ML, D’Angelo JA, Grimes ZM, Fiebiger E, Dickinson BL (2012) The cystine/glutamate antiporter regulates indoleamine 2,3-dioxygenase protein levels and enzymatic activity in human dendritic cells. Am J Clin Exp Immunol 1:113–123
McLaren JE, Ramji DP (2009) Interferon: a master regulator of atherosclerosis. Cytokine Growth Factor Rev 20:125–135
Melillo G, Cox GW, Biragyn A, Sheffler LA, Varesio L (1994) Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acid. J Biol Chem 269:8128–8133
Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F (2013) Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14:877–882
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW, Kaplan GG (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142:46–54
Moseman EA, Liang X, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ, Blazar BR, Chen W (2004) Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol 173:4433–4442
Mueller T, Podolsky DK (2005) Nucleotide-binding-oligomerization domain proteins and toll-like receptors: sensors of the inflammatory bowel diseases’ microbial environment. Curr Opin Gastroenterol 21:419–425
Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11:312–319
Munn DH, Mellor AL (2006) The tumor-draining lymph node as an immune-privileged site. Immunol Rev 213:146–158
Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117:1147–1154
Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22:633–642
Murr C, Fuith LC, Widner B, Wirleitner B, Baier-Bitterlich G, Fuchs D (1999) Increased neopterin concentrations in patients with cancer: indicator of oxidative stress? Anticancer Res 19:1721–1728
Nagatsu T, Ichinose H (1999) Regulation of pteridine-requiring enzymes by the cofactor tetrahydrobiopterin. Mol Neurobiol 19:79–96
Niederwieser D, Fuchs D, Hausen A, Judmaier G, Reibnegger G, Wachter H, Huber C (1985) Neopterin as a new biochemical marker in the clinical assessment of ulcerative colitis. Immunobiology 170:320–326
Niinisalo P, Raitala A, Pertovaara M, Oja SS, Lehtimäki T, Kähönen M, Reunanen A, Jula A, Moilanen L, Kesäniemi YA, Nieminen MS, Hurme M (2008) Indoleamine 2,3-dioxygenase activity associates with cardiovascular risk factors: the Health 2000 study. Scand J Clin Lab Invest 68:767–770
Niinisalo P, Oksala N, Levula M, Pelto-Huikko M, Jarvinen O, Salenius JP, Kytomaki L, Soini JT, Kahonen M, Laaksonen R, Hurme M, Lehtimaki T (2010) Activation of indoleamine 2,3-dioxygenase-induced tryptophan degradation in advanced atherosclerotic plaques: Tampere vascular study. Ann Med 42:55–63
Noh KT, Chae SH, Chun SH, Jung ID, Kang HK, Park YM (2013) Resveratrol suppresses tumor progression via the regulation of indoleamine 2,3-dioxygenase. Biochem Biophys Res Commun 431:348–353
Ohman L, Isaksson S, Lindmark AC, Posserud I, Stotzer PO, Strid H, Sjövall H, Simrén M (2009) T-cell activation in patients with irritable bowel syndrome. Am J Gastroenterol 104:1205–1212
Oxenkrug GF (2007) Genetic and hormonal regulation of tryptophan kynurenine metabolism: implications for vascular cognitive impairment, major depressive disorder, and aging. Ann N Y Acad Sci 1122:35–49
Oxenkrug GF (2010) Metabolic syndrome, age-associated neuroendocrine disorders, and dysregulation of tryptophan-kynurenine metabolism. Ann N Y Acad Sci 1199:1–14
Oxenkrug G (2013) Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol 48:294–301
Oxenkrug G, Tucker KL, Requintina P, Summergrad P (2011) Neopterin, a marker of interferon-gamma-inducible inflammation, correlates with pyridoxal-5′-phosphate, waist circumference, HDL-cholesterol, insulin resistance and mortality risk in adult Boston community dwellers of Puerto Rican origin. Am J Neuroprot Neuroregen 3:48–52
Pae HO, Oh GS, Lee BS, Rim JS, Kim YM, Chung HT (2006) 3-Hydroxyanthranilic acid, one of L-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells. Atherosclerosis 187:274–284
Pandi-Perumal SR, BaHammam AS, Brown GM, Spence DW, Bharti VK, Kaur C, Hardeland R, Cardinali DP (2013) Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res 23:267–300
Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036
Pedersen ER, Midttun Ø, Ueland PM, Schartum-Hansen H, Seifert R, Igland J, Nordrehaug JE, Ebbing M, Svingen G, Bleie Ø, Berge R, Nygård O (2011) Systemic markers of interferon-γ-mediated immune activation and long-term prognosis in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol 31:698–704
Penberthy TW (2007) Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. Curr Drug Metab 8:245–266
Pertovaara M, Raitala A, Juonala M, Lehtimäki T, Huhtala H, Oja SS, Jokinen E, Viikari JS, Raitakari OT, Hurme M (2007) Indoleamine 2,3-dioxygenase enzyme activity correlates with risk factors for atherosclerosis: the Cardiovascular Risk in Young Finns Study. Clin Exp Immunol 148:106–111
Peterson TE, Katusic ZS (2005) Transcribing the cross-talk of cytokine-induced tetrahydrobiopterin synthesis in endothelial cells. Circ Res 96:141–143
Platten M, Ho PP, Youssef S, Fontoura P, Garren H, Hur EM, Gupta R, Lee LY, Kidd BA, Robinson WH, Sobel RA, Selley ML, Steinman L (2005) Treatment of auto-immune neuroinflammation with a synthetic tryptophan metabolite. Science 310:850–855
Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM (1992) Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 267:24173–24176
Prior C, Bollbach R, Fuchs D, Hausen A, Judmaier G, Niederwieser D, Reibnegger G, Rotthauwe HW, Werner ER, Wachter H (1986) Urinary neopterin, a marker of clinical activity in patients with Crohn’s disease. Clin Chim Acta 155:11–21
Radhakrishnan S, Cabrera R, Schenk EL, Nava-Parada P, Bell MP, Van Keulen VP, Marler RJ, Felts SJ, Pease LR (2008) Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo. J Immunol 181:3137–3147
Rana SV, Sharma S, Sinha SK, Parsad KK, Malik A, Singh K (2012) Pro-inflammatory and anti-inflammatory cytokine response in diarrhoea-predominant irritable bowel syndrome patients. Trop Gastroenterol 33:251–256
Ray KK, Morrow DA, Sabatine MS, Shui A, Rifai N, Cannon CP, Braunwald E (2007) Long-term prognostic value of neopterin: a novel marker of monocyte activation in patients with acute coronary syndrome. Circulation 115:3071–3078
Riedl A, Schmidtmann M, Stengel A, Goebel M, Wisser AS, Klapp BF, Mönnikes H (2008) Somatic comorbidities of irritable bowel syndrome: a systematic analysis. J Psychosom Res 64:573–582
Robinson CM, Hale PT, Carlin JM (2005) The role of IFN-gamma and TNF-alpha-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase. J Interferon Cytokine Res 25:20–30
Rockwell CE, Zhang M, Fields PE, Klaassen CD (2012) Th2 skewing by activation of Nrf2 in CD4(+) T cells. J Immunol 188:1630–1637
Ronen N, Livne E, Gross B (1999) Oxidative damage in rat tissue following excessive 1-tryptophan and atherogenic diets. Adv Exp Med Biol 467:497–505
Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA (2006) Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med 8:1–27
Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352
Sakaguchi S (2006) Regulatory T cells. Springer Semin Immunopathol 28:1–2
Santhanam L, Lim HK, Lim HK, Miriel V, Brown T, Patel M, Balanson S, Ryoo S, Anderson M, Irani K, Khanday F, Di Costanzo L, Nyhan D, Hare JM, Christianson DW, Rivers R, Shoukas A, Berkowitz DE (2007) Inducible no synthase dependent s-nitrosylation and activation of arginase1 contribute to age-related endothelial dysfunction. Circ Res 101:692–702
Schröcksnadel K, Wirleitner B, Winkler C, Fuchs D (2006) Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta 364:82–90
Schroecksnadel K, Winkler C, Wirleitner B, Schennach H, Fuchs D (2005a) Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro. Clin Exp Immunol 140:41–45
Schroecksnadel K, Winkler C, Fuith LC, Fuchs D (2005b) Tryptophan degradation in patients with gynecological cancer correlates with immune activation. Cancer Lett 223:323–329
Schroecksnadel K, Frick B, Winkler C, Fuchs D (2006) Crucial role of interferon-gamma and stimulated macrophages in cardiovascular disease. Curr Vasc Pharmacol 4:205–213
Schroecksnadel S, Sucher R, Kurz K, Fuchs D, Brandacher G (2011) Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells. Transpl Immunol 25:119–123
Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303:1–10
Scully P, McKernan DP, Keohane J, Groeger D, Shanahan F, Dinan TG, Quigley EM (2010) Plasma cytokine profiles in females with irritable bowel syndrome and extra-intestinal co-morbidity. Am J Gastroenterol 105:2235–2243
Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, Azuma M, Blazar BR, Mellor AL, Munn DH (2007) Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117:2570–2582
Sharma MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler P, Mellor AL, He Y, Munn DH (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113:6102–6111
Shintaku H (2002) Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab 3:123–131
Shufflebotham J, Hood S, Hendry J, Hince DA, Morris K, Nutt D, Probert C, Potokar J (2006) Acute tryptophan depletion alters gastrointestinal and anxiety symptoms in irritable bowel syndrome. Am J Gastroenterol 101:2582–2587
Sikander A, Rana SV, Prasad KK (2009) Role of serotonin in gastrointestinal motility and irritable bowel syndrome. Clin Chim Acta 403:47–55
Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT (2012) Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol 351:152–166
Smith CJ, Santhanam L, Bruning RS, Stanhewicz A, Berkowitz DE, Holowatz LA (2011) Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans. Hypertension 58:935–942
Soliman H, Mediavilla-Varela M, Antonia S (2010) Indoleamine 2,3-dioxygenase: is it an immune suppressor? Cancer J 16:354–359
Sørensen RB, Berge-Hansen L, Junker N, Hansen CA, Hadrup SR, Schumacher TN, Svane IM, Becker JC, Thor Straten P, Andersen MH (2009) The immune system strikes back: cellular immune responses against indoleamine 2,3-dioxygenase. PLoS One 4:e6910
Sørensen RB, Hadrup SR, Svane IM, Hjortsø MC, Thor Straten P, Andersen MH (2011) Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 117:2200–2210
Sperner-Unterweger B, Neurauter G, Klieber M, Kurz K, Meraner V, Zeimet A, Fuchs D (2011) Enhanced tryptophan degradation in patients with ovarian carcinoma correlates with several serum soluble immune activation markers. Immunobiology 216:296–301
Stone TW (2001) Endogenous neurotoxins from tryptophan. Toxicon 39:61–73
Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, Katayama I, Ezoe S, Kanakura Y, Sato E, Fukumori Y, Karbach J, Jäger E, Sakaguchi S (2013) Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A 110:17945–17950
Tabas I, Williams KJ, Boren J (2007) Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116:1832–1844
Taylor MW, Feng GS (1991) Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 5:2516–2522
Theofylaktopoulou D, Midttun Ø, Ulvik A, Ueland PM, Tell GS, Vollset SE, Nygård O, Eussen SJ (2013) A community-based study on determinants of circulating markers of cellular immune activation and kynurenines: the Hordaland Health Study. Clin Exp Immunol 173:121–130
Tournier C, Thomas G, Pierre J, Jacquemin C, Pierre M, Saunier B (1997) Mediation by arachidonic acid metabolites of the H2O2-induced stimulation of mitogen-activated protein kinases (extracellular-signal-regulated kinase and c-Jun NH2-terminal kinase). Eur J Biochem 244:587–595
Travers MT, Gow IF, Barber MC, Thomson J, Shennan DB (2004) Indoleamine 2,3-dioxygenase activity and L-tryptophan transport in human breast cancer cells. Biochim Biophys Acta 1661:106–112
Urbańska EM, Luchowski P, Luchowska E et al (2006) Serum kynurenic acid positively correlates with cardiovascular disease risk factor, homocysteine: a study in stroke patients. Pharmacol Rep 58:507–511
Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9:1269–1274
van Donkelaar EL, Blokland A, Ferrington L, Kelly PA, Steinbusch HW, Prickaerts J (2011) Mechanism of acute tryptophan depletion: is it only serotonin? Mol Psychiatry 16:695–713
Vesely MD, Schreiber RD (2013) Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann N Y Acad Sci 1284:1–5
Von Eynatten M, Breitling LP, Roos M, Baumann M, Rothenbacher D, Brenner H (2012) Circulating adipocyte fatty acid-binding protein levels and cardiovascular morbidity and mortality in patients with coronary heart disease: a 10-year prospective study. Arterioscler Thromb Vasc Biol 32:2327–2335
Wakabayashi N, Shin S, Slocum SL, Agoston ES, Wakabayashi J, Kwak MK, Misra V, Biswal S, Yamamoto M, Kensler TW (2010) Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci Signal 3:ra52
Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR, Kapoor V, Celermajer DS, Mellor AL, Keaney JF Jr, Hunt NH, Stocker R (2010) Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 16:279–285
Weber WP, Feder-Mengus C, Chiarugi A, Rosenthal R, Reschner A, Schumacher R, Zajac P, Misteli H, Frey DM, Oertli D, Heberer M, Spagnoli GC (2006) Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines. Eur J Immunol 36:296–304
Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D (2002) Neopterin production, tryptophan degradation, and mental depression–what is the link? Brain Behav Immun 16:590–595
Wirleitner B, Neurauter G, Schrocksnadel K, Frick B, Fuchs D (2003) Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects. Curr Med Chem 10:1581–1591
Wolf AM, Wolf D, Rumpold H, Moschen AR, Kaser A, Obrist P, Fuchs D, Brandacher G, Winkler C, Geboes K, Rutgeerts P, Tilg H (2004) Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease. Clin Immunol 113:47–55
Wolowczuk I, Hennart B, Leloire A, Bessede A, Soichot M, Taront S, Caiazzo R, Raverdy V, Pigeyre M, ABOS Consortium, Guillemin GJ, Allorge D, Pattou F, Froguel P, Poulain-Godefroy O (2012) Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone. Am J Physiol Regul Integr Comp Physiol 303:R135–43
Xu J, Yu S, Sun AY, Sun GY (2003) Oxidant-mediated AA release from astrocytes involves cPLA(2) and iPLA(2). Free Radic Biol Med 34:1531–1543
Yamaguchi T, Sakaguchi S (2006) Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol 16:115–123
Zamanakou M, Germenis AE, Karanikas V (2007) Tumor immune escape mediated by indoleamine 2,3-dioxygenase. Immunol Lett 111:69–75
Zhang L, Ovchinnikova O, Jönsson A, Lundberg AM, Berg M, Hansson GK, Ketelhuth DF (2012) The tryptophan metabolite 3-hydroxyanthranilic acid lowers plasma lipids and decreases atherosclerosis in hypercholesterolaemic mice. Eur Heart J 33:2025–2034
Zhou L, Chen H, Wen Q, Zhang Y (2012) Indoleamine 2,3-dioxygenase expression in human inflammatory bowel disease. Eur J Gastroenterol Hepatol 24:695–701
Zhu H, Jia Z, Zhang L, Yamamoto M, Misra HP, Trush MA, Li Y (2008) Antioxidants and phase 2 enzymes in macrophages: regulation by Nrf2 signaling and protection against oxidative and electrophilic stress. Exp Biol Med (Maywood) 233:463–474
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Engin, A.B. (2015). Evaluation of Tryptophan Metabolism in Chronic Immune Activation. In: Engin, A., Engin, A. (eds) Tryptophan Metabolism: Implications for Biological Processes, Health and Disease. Molecular and Integrative Toxicology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15630-9_6
Download citation
DOI: https://doi.org/10.1007/978-3-319-15630-9_6
Publisher Name: Humana Press, Cham
Print ISBN: 978-3-319-15629-3
Online ISBN: 978-3-319-15630-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)