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Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders

  • Basic Neurosciences, Genetics and Immunology - Review Article
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Abstract

This review of literature and our data suggests that up-regulated production of interferon-gamma (IFNG) in periphery and brain triggers a merger of tryptophan (TRY)–kynurenine (KYN) and guanine–tetrahydrobiopterin (BH4) metabolic pathways into inflammation cascade involved in aging and aging-associated medical and psychiatric disorders (AAMPD) (metabolic syndrome, depression, vascular cognitive impairment). IFNG-inducible KYN/pteridines inflammation cascade is characterized by up-regulation of nitric oxide synthase (NOS) activity (induced by KYN) and decreased formation of NOS cofactor, BH4, that results in uncoupling of NOS that shifting arginine from NO to superoxide anion production. Superoxide anion and free radicals among KYN derivatives trigger phospholipase A2-arachidonic acid cascade associated with AAMPD. IFNG-induced up-regulation of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of TRY–KYN pathway, decreases TRY conversion into serotonin (substrate of antidepressant effect) and increases production of KYN associated with diabetes [xanthurenic acid (XA)], anxiety (KYN), psychoses and cognitive impairment (kynurenic acid). IFNG-inducible KYN/pteridines inflammation cascade is impacted by IFNG (+874) T/A genotypes, encoding cytokine production. In addition to literature data on KYN/TRY ratio (IDO activity index), we observe neopterin levels (index of activity of rate-limiting enzyme of guanine–BH4 pathway) to be higher in carriers of high (T) than of low (A) producers alleles; and to correlate with AAMPD markers (e.g., insulin resistance, body mass index, mortality risk), and with IFN-alpha-induced depression in hepatitis C patients. IFNG-inducible cascade is influenced by environmental factors (e.g., vitamin B6 deficiency increases XA formation) and by pharmacological agents; and might offer new approaches for anti-aging and anti-AAMPD interventions.

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References

  • Allegra A, Corica F, Di Cesare E et al (1992) The influence of hypercholesterolemia on some aspects of immune pattern in the elderly. Arch Gerontol Geriatr 15:13–19

    Article  CAS  PubMed  Google Scholar 

  • Anuradha B, Rakh SS, Ishaq M et al (2008) Interferon-gamma low producer genotype +874 overrepresented in Bacillus Calmette-Guerin nonresponding children. Pediatr Infect Dis J 27:325–329

    Article  PubMed  Google Scholar 

  • Bachurin S et al (1999) N-acetylserotonin, melatonin and their derivatives improve cognition and protect against beta-amyloid-induced neurotoxicity. Ann N Y Acad Sci 890:155–166

    Article  CAS  PubMed  Google Scholar 

  • Baran H et al (1996) Increased kynurenic acid levels and decreased brain kynurenine aminotransferase I in patients with Down syndrome. Life Sci 58:1891–1899

    Article  CAS  PubMed  Google Scholar 

  • Beedholm-Ebsen R, van de Wetering K, Hardlei T et al (2010) Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin. Blood 115:1632–1639

    Article  CAS  PubMed  Google Scholar 

  • Bender DA, Njagi EN, Danielian PS (1990) Tryptophan metabolism in vitamin B6-deficient mice. Br J Nutr 63:27–36

    Article  CAS  PubMed  Google Scholar 

  • Biolo G, Amoroso A, Savoldi S et al (2006) Association of interferon-gamma +874A polymorphism with reduced long-term inflammatory response in haemodialysis patients. Nephrol Dial Transplant 21:1317–1322

    Article  CAS  PubMed  Google Scholar 

  • Bozdemir AE, Barutcuoglu B, Dereli D et al (2006) C-reactive protein and neopterin levels in healthy non-obese adults. Clin Chem Lab Med 44:317–321

    Article  CAS  PubMed  Google Scholar 

  • Brandacher G (2007) Chronic immune activation underlies morbid obesity: is IDO a key player? Curr Drug Metab 8:289–295

    Article  CAS  PubMed  Google Scholar 

  • Brandacher G et al (2006) Bariatric surgery cannot prevent tryptophan depletion due to chronic immune activation in morbidly obese patients. Obes Surg 16:541–548

    Article  PubMed  Google Scholar 

  • Breum L, Rasmussen MH, Hilsted J, Fernstrom JD (2003) Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr 77:1112–1118

    CAS  PubMed  Google Scholar 

  • Brustolim D et al (2006) A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice. Int Immunopharmacol 6:903–990

    Article  CAS  PubMed  Google Scholar 

  • Cady SG, Sono M (1991) 1-Methyl-dl-tryptophan, beta-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch Biochem Biophys 291:326–333

    Article  CAS  PubMed  Google Scholar 

  • Campayo A, de Jonge P, Roy JF, Saz P, de la Camara C, Quintamilla MA, Marcos G, Santabárbara J, Lobo A (2010) Depressive disorder and incident diabetes mellitus: the effect of characteristics of depression. Am J Psychiatry 167:580–588

    Article  PubMed  Google Scholar 

  • Chiarugi A, Dello Sbarba P, Paccagnini A et al (2000) Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages. J Leukoc Biol 68:260–266

    CAS  PubMed  Google Scholar 

  • Dang Y et al (2000) Comparative effects of oxygen on indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase of the kynurenine pathway. Free Radic Biol Med 28:615–624

    Article  CAS  PubMed  Google Scholar 

  • Deguchi K et al (2001) Postmenopausal changes in production of type 1 and type 2 cytokines and the effects of hormone replacement therapy. Menopause 8:266–273

    Article  CAS  PubMed  Google Scholar 

  • Diamondstone LS, Tollerud DJ, Fuchs D et al (1994) Factors influencing serum neopterin and beta 2-microglobulin levels in a healthy diverse population. J Clin Immunol 14:368–374

    Article  CAS  PubMed  Google Scholar 

  • Dilman VM (1971) Age-associated elevation of hypothalamic threshold to feedback control, and its role in development, ageing, and disease. Lancet 1(7711):1211–1219

    Article  CAS  PubMed  Google Scholar 

  • Dilman VM (1994) Development, aging and disease: a new rationale for an intervention strategy. Harvard Acad. Publ, Zurich

    Google Scholar 

  • Dilman VM, Lapin IP, Oxenkrug GF (1979) Serotonin and aging. In: Essman W (ed) Serotonin in health and disease, vol 5. Spectrum Press, London, pp 111–123

    Google Scholar 

  • Dinarello CA (2007) Interleukin-18 and the pathogenesis of inflammatory diseases. Semin Nephrol 27:98–114

    Article  CAS  PubMed  Google Scholar 

  • Fahey JL, Schnelle JF et al (2000) Distinct categories of immunologic changes in frail elderly. Mech Ageing Dev 115:1–20

    Article  CAS  PubMed  Google Scholar 

  • Filipovic R, Zecevic N (2008) Neuroprotective role of minocycline in co-cultures of human fetal neurons and microglia. Exp Neurol 211:41–51

    Article  CAS  PubMed  Google Scholar 

  • Finkelstein JA (1982) Brain serotonergic activity and plasma amino acid levels in genetically obese Zucker rats. Pharmacol Biochem Behav 17:939–944

    Article  CAS  PubMed  Google Scholar 

  • Fredrickson DS (1964) The inheritance of high density lipoprotein deficiency (Tangier disease). J Clin Invest 43:228–236

    Article  CAS  PubMed  Google Scholar 

  • Frick B, Schroecksnadel K, Neurauter G (2004) Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clin Biochem 37:684–687

    Article  CAS  PubMed  Google Scholar 

  • Fridman AL, Tainsky MA (2008) Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene 27:5975–5987

    Article  CAS  PubMed  Google Scholar 

  • Fuchs D, Avanzas P et al (2009) The role of neopterin in atherosclerosis and cardiovascular risk assessment. Curr Med Chem 16:4644–4653

    Article  CAS  PubMed  Google Scholar 

  • Fulop T (2006) The metabolic syndrome. Pathol Biol 54:375–386

    Article  CAS  PubMed  Google Scholar 

  • Gál EM, Sherman AD (1980) l-Kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res 5:223–239

    Article  PubMed  Google Scholar 

  • Grammer TB, Fuchs D, Boehm BO et al (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

    Article  CAS  PubMed  Google Scholar 

  • Gramsbergen JB, Schmidt W, Turski WA, Schwarcz R (1992) Age-related changes in kynurenic acid production in rat brain. Brain Res 588:1–5

    Article  CAS  PubMed  Google Scholar 

  • Griffin DE, Wesselingh SL, McArthur JC (1994) Elevated central nervous system prostaglandins in human immunodeficiency virus-associated dementia. Ann Neurol 35:592–597

    Article  CAS  PubMed  Google Scholar 

  • Guillemin GJ, Brew BJ (2002) Implications of the kynurenine pathway and quinolinic acid in Alzheimer’s disease. Redox Rep 7:199–206

    Article  CAS  PubMed  Google Scholar 

  • Han Q, Tao C, Tagle DA, Li J (2010) Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell Mol Life Sci 67:353–368

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto K (2008) Microglial activation in schizophrenia and minocycline treatment. Prog Neuropsychopharmacol Biol Psychiatry 32:1758–1759

    Article  CAS  PubMed  Google Scholar 

  • Hattori M, Kotake Y, Kotake Y (1984) Studies on the urinary excretion of xanthurenic acid in diabetics. Acta Vitaminol Enzymol 6:221–228

    CAS  PubMed  Google Scholar 

  • Hayaishi O (1976) Properties and function of indoleamine 2,3-dioxygenase. Properties and function of indoleamine 2,3-dioxygenase. J Biochem (Tokyo) 79:13P–21P

    CAS  Google Scholar 

  • Holvoet P (2008) Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease. Verh K Acad Geneeskd Belg 70:193–219

    CAS  PubMed  Google Scholar 

  • Janssen I et al (2008) Menopause and metabolic syndrome: the studies of women’s health across the nation. Arch Intern Med 168:1568–1575

    Article  CAS  PubMed  Google Scholar 

  • Kenis G, Maes M (2002) Effects of antidepressants on the production of cytokines. Int J Neuropsychopharmacol 5:401–412

    Article  CAS  PubMed  Google Scholar 

  • Kim KS, Kang KW, Seu YB et al (2009) Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. Mech Ageing Dev 130:179–188

    Article  CAS  PubMed  Google Scholar 

  • Kincses ZT, Toldi J, Vécsei L (2010) Kynurenines, neurodegeneration and Alzheimer’s disease. J Cell Mol Med

  • Kirov G, Lowry CA, Stephens M, Oldfield S, O’Donovan MC, Lightman SL, Owen MJ (2001) Screening ABCG1, the human homologue of the Drosophila white gene, for polymorphisms and association with bipolar affective disorder. Mol Psychiatry 6(6):671–677

    Article  CAS  PubMed  Google Scholar 

  • Knight H et al (2009) A cytogenic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. Am J Hum Genet 85:833–846

    Article  CAS  PubMed  Google Scholar 

  • Koga M et al (2007) Postnatal blocking of interferon-gamma function prevented atherosclerotic plaque formation in apolipoprotein E-knockout mice. Hypertens Res 30:259–267

    Article  CAS  PubMed  Google Scholar 

  • Kotaki Y, Ueda T, Mori T, Igaki S, Hattori M (1975) Abnormal tryptophan metabolism and experimental diabetes by xanthurenic acid (XA). Acta Vitaminol Enzymol 29:236–239

    Google Scholar 

  • Lann D, LeRoith D (2007) Insulin resistance as the underlying cause for the metabolic syndrome. Med Clin N Am 91:1063–1077

    Article  CAS  PubMed  Google Scholar 

  • Lapin IP (1996) Kynurenines and anxiety. Adv Exp Med Biol 398:191–194

    CAS  PubMed  Google Scholar 

  • Lapin IP (1998) Antagonism of kynurenic acid to anxiogens in mice. Life Sci 63:231–236

    Article  Google Scholar 

  • Lapin IP (2003) Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety. Adv Exp Med Biol 527:121–125

    CAS  PubMed  Google Scholar 

  • Lapin IP, Oxenkrug GF (1969) Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet 1:32–39

    Google Scholar 

  • Lapin IP et al (1998) Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA and pentylenetetrazole in mice. J Pineal Res 24:215–218

    Article  CAS  PubMed  Google Scholar 

  • Ledochowski M, Murr C, Widner B, Fuchs D (1999) Association between insulin resistance, body mass and neopterin concentrations. Clin Chim Acta 282(1–2):115–123

    Article  CAS  PubMed  Google Scholar 

  • Levkovitz Y, Mendlovich S et al (2010) A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 71:138–149

    Article  CAS  PubMed  Google Scholar 

  • Li LO, Hu YF, Wang L, Mitchell M, Berger A, Coleman RA (2010) Early hepatic insulin resistance in mice: a metabolomics analysis. Mol Endocrinol 24:657–666

    Article  CAS  PubMed  Google Scholar 

  • Lio D et al (2002) Allele frequencies of +874T-A single nucleotide polymorphism at the first intron of interferon-gamma gene in a group Italian centenarians. Exp Gerontol 37:315–319

    Article  CAS  PubMed  Google Scholar 

  • Mackenzie SM, Brooker MR, Gill TR, Cox GB, Howells AJ, Ewart GD (1999) Mutations in the white gene of Drosophila melanogaster affecting ABC transporters that determine eye colouration. Biochim Biophys Acta 1419:173–185

    Article  CAS  PubMed  Google Scholar 

  • Manev G, Manev R (2007) 5-lipoxygenase as a possible biological link between depressive symptoms and atherosclerosis. Arch Gen Psychiatry 64:1333

    Article  PubMed  Google Scholar 

  • Mattei J, Parnell LD et al (2009) Disparities in allele frequencies and population differentiation for 101 disease-associated single nucleotide polymorphisms between Puerto Ricans and non-Hispanic whites. BMC Genet 10:45

    Article  PubMed  CAS  Google Scholar 

  • Meier CA, Thalmann S (2007) White adipose tissue, inflammation and atherosclerosis. Bull Acad Natl Med 191:897–908

    CAS  PubMed  Google Scholar 

  • Melillo G, Cox DW, Biragyn A, Sheffler LA (1994) Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acid. J Biol Chem 269:8128–8813

    CAS  PubMed  Google Scholar 

  • Merete C, Falcon LM, Tucker KL (2008) Vitamin B6 is associated with depressive symptomatology in Massachusetts elders. J Am Coll Nutr 27:421–427

    CAS  PubMed  Google Scholar 

  • Meyramov G, Korchin V, Kocheryzkina N (1984) Diabetogenic activity of xanthurenic acid determined by its chelating properties? Acta Vitaminol Enzymol 6:221–228

    Google Scholar 

  • Molina-Hernandez M et al (2008) Antidepressant-like actions of minocycline combined with several glutamate antagonists. Prog Neuropsychopoharmacol Biol Psychiatry 32:380–386

    Article  CAS  Google Scholar 

  • Moroni F, Russi P, Carlá V, Lombardi G (1998) Kynurenic acid is present in the rat brain and its content increases during development and aging processes. Neurosci Lett 94:145–150

    Article  Google Scholar 

  • Morris MS, Sakakeeny L, Jacques PF, Picciano MF, Selhub J (2010) Vitamin B-6 intake is inversely related to, and the requirement is affected by, inflammation status. J Nutr 140:103–110

    Article  CAS  PubMed  Google Scholar 

  • Müller N, Myint AM, Schwarz MJ (2009) The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders—relation to drug treatment. Dialogues Clin Neurosci 11:319–332

    PubMed  Google Scholar 

  • Németh H, Toldi J, Vécsei L (2005) Role of kynurenines in the central and peripheral nervous systems. Curr Neurovasc Res 2:249–260

    Article  PubMed  Google Scholar 

  • Nicole NH, Perfield JW et al (2008) Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology 150:2161–2168

    Article  CAS  Google Scholar 

  • Niinisalo P et al (2008) Indoleamine 2,3-dioxygenase activity associates with cardiovascular risk factors: the Health 2000 study. Scand J Clin Lab Invest 2008(68):767–770

    Article  CAS  Google Scholar 

  • Oettl K, Reibnegger G (2005) Pteridine derivatives as modulators of oxidative stress. Clin Biochem 38:916–919

    Article  CAS  Google Scholar 

  • Oxenkrug GF (1991) The acute effect of monoamine oxidase inhibitors on serotonin conversion to melatonin. In: Sandler M, Coppen A, Harnett S (eds) 5-hydroxytryptamine in psychiatry: a spectrum of ideas. Oxford University Press, New York, pp 98–109

    Google Scholar 

  • Oxenkrug GF (2005) Antioxidant effects of N-acetylserotonin: possible mechanisms and clinical implications. Ann N Y Acad Sci 1053:334–347

    Article  CAS  PubMed  Google Scholar 

  • Oxenkrug GF (2007) Genetic and hormonal regulation of the kynurenine pathway of tryptophan metabolism: new target for clinical intervention in vascular dementia, depression and aging. Ann N Y Acad Sci 1122:35–49

    Article  CAS  PubMed  Google Scholar 

  • Oxenkrug GF (2010a) Metabolic syndrome, age-associated neuroendocrine disorders and dysregulation of tryptophan–kynurenine pathway metabolism. Ann N Y Acad Sci 1199:1–14

    Article  CAS  PubMed  Google Scholar 

  • Oxenkrug GF (2010b) Tryptophan–kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: “the serotonin hypothesis” revisited 40 years later. Israel J Psychiatry 47(1):56–63

    Google Scholar 

  • Oxenkrug GF (2010c) The extended life span of Drosophila melanogaster eye-color (white and vermilion) mutants with impaired formation of kynurenine. J Neural Transm 117:23–26

    Article  CAS  PubMed  Google Scholar 

  • Oxenkrug GF, Lapin IP (1974) Kynurenine pathway of the metabolism of tryptophan and its possible neuropharmacologic role. In: Yakovelev V (ed) Chemistry and pharmacology of indole compounds. Stinza, Kishinev, pp 5–18

    Google Scholar 

  • Oxenkrug GF, Summergrad P (2010) Ramelteon attenuates age-associated hypertension and weight gain in spontaneously hypertension rats. Ann N Y Acad Sci 1199:114–120

    Article  CAS  PubMed  Google Scholar 

  • Oxenkrug G, Perianaygam M et al (2010) Interferon-gamma (+874) T/A genotypes and risk of IFN-alpha-induced depression (submitted)

  • Oxenkrug GF, Tucker KJ et al (2010) Neopterin, an interferon-related marker of inflammation, correlates with metabolic syndrome markers and mortality risk in adult Boston community dwellers of Puerto Rican origin. Ann N Y Acad Sci (submitted)

  • Pacifico L et al (2006) Increased T-helper interferon-gamma-secreting cells in obese children. Eur J Endocrinol 154:691–697

    Article  CAS  PubMed  Google Scholar 

  • Pae CU et al (2008) Does minocycline have antidepressant effect? Biomed Pharmacother 62:308–311

    Article  CAS  PubMed  Google Scholar 

  • Pearson SJ, Reynolds GP (1991) Determination of 3-hydroxykynurenine in human brain and plasma by high-performance liquid chromatography with electrochemical detection. Increased concentrations in hepatic encephalopathy. J Chromatogr 565:436–440

    Article  CAS  PubMed  Google Scholar 

  • Perez-Severiano F, Escalante B, Rios C (1998) Nitric oxide synthase inhibition prevents acute quinolinate-induced striatal neurotoxicity. Neurochem Res 23:1297–1302

    Article  CAS  PubMed  Google Scholar 

  • Perianayagam MC et al (2005) Immune modulating effects of melatonin, N-acetylserotonin and N-acetyl dopamine. Ann N Y Acad Sci 1053:386–393

    Article  CAS  PubMed  Google Scholar 

  • Perianayagam M, Oxenkrug G (2010) Interferon-gamma (+874) single nucleotide polymorphism and human plasma neopterin levels (submitted)

  • Pertovaara M, Raitala A, Lehtimäki T (2006) Indoleamine 2,3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality. Mech Ageing Dev 127:497–499

    CAS  PubMed  Google Scholar 

  • Pertovaara M et al (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

    Article  CAS  PubMed  Google Scholar 

  • Peterson TE, Katusic ZS (2005) Transcribing the cross-talk of cytokine-induced tetrahydrobiopterin synthesis in endothelial cells. Circ Res 96:141–143

    Article  CAS  PubMed  Google Scholar 

  • Pitche PT (2005) [Pellagra] Sante. 15:205–208

    Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Poynter ME, Daynes RA (1999) Age-associated alterations in splenic iNOS regulation: influence of constitutively expressed IFN-gamma and correction following supplementation with PPARalpha activators or vitamin E. Cell Immunol 195:127–136

    Article  CAS  PubMed  Google Scholar 

  • Prakhie IV, Oxenkrug GF (1998) The effect of nifedipine, Ca++ antagonist, on activity of MAO inhibitors, N-acetylserotonin and melatonin in the mouse tail suspension test. Int J Neuropsychopharmacol 1:35–40

    Article  CAS  PubMed  Google Scholar 

  • Pravica V, Perrey C, Stevens A et al (2000) A single nucleotide polymorphism in the first intron of the human INFG gene: absolute correlation with a polymorphic CA micro marker of high INFG gene. Hum Immunol 61:8333–8366

    Article  Google Scholar 

  • Raitala A, Pertovaara M, Karjalainen J et al (2005) Association of interferon-gamma +874(T/A) single nucleotide polymorphism with the rate of tryptophan catabolism in healthy individuals. Scand J Immunol 61:387–390

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Requintina PJ, Oxenkrug GF (2003) Differential effects of lipopolysaccharide on lipid peroxidation in F344N, SHR rats and BALB/C mice and protection of melatonin and NAS against its toxicity. Ann N Y Acad Sci 993:325–333

    Article  CAS  PubMed  Google Scholar 

  • Riederer P, Reynolds GP (1981) Determination of a wide range of urinary amine metabolites using a simple high-performance liquid chromatographic technique. J Chromatogr 225:179–184

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Rocha VZ et al (2008) Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res 103:467–476

    Article  CAS  PubMed  Google Scholar 

  • Rodríguez MI, Escames G, López LC et al (2007) Chronic melatonin treatment reduces the age-dependent inflammatory process in senescence-accelerated mice. J Pineal Res 42:272–279

    Article  PubMed  CAS  Google Scholar 

  • Ryu JK, Choi HB, McLarnon JG (2006) Combined minocycline plus pyruvate treatment enhances effects of each agent to inhibit inflammation, oxidative damage, and neuronal loss in an excitotoxic animal model of Huntington’s disease. Neuroscience 141:1835–1848

    Article  CAS  PubMed  Google Scholar 

  • Samsonova ML, Oxenkrug GF (1972) Inhibition of substrate induction of TRY-pyrrolase in liver and increase in the content in 5-HT in brain under action of inhibitors of MAO. Vopr Med Khim 17:198–201

    Google Scholar 

  • Sarkar SA, Wong R, Hackl SI et al (2007) Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human islets. Diabetes 56:72–79

    Article  CAS  PubMed  Google Scholar 

  • Schennach H, Murr C, Gächter E et al (2002) Factors influencing serum neopterin concentrations in a population of blood donors. Clin Chem 48:643–645

    CAS  PubMed  Google Scholar 

  • Schoedon G, Troppmair J, Adolf G et al (1986) Interferon-gamma enhances biosynthesis of pterins in peripheral blood mononuclear cells by induction of GTP-cyclohydrolase I activity. J Interferon Res 6:697–703

    CAS  PubMed  Google Scholar 

  • Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303:1–10

    Article  CAS  PubMed  Google Scholar 

  • Schwieler L, Erhardt S, Nilsson L et al (2006) Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons—possible involvement of endogenous kynurenic acid. Synapse 59:290–298

    Article  CAS  PubMed  Google Scholar 

  • Shen J, Lai CQ, Mattei J, Ordovas JM, Tucker KL (2010) Association of vitamin B-6 status with inflammation, oxidative stress, and chronic inflammatory conditions: the Boston Puerto Rican Health Study. Am J Clin Nutr 91:337–342

    Article  CAS  PubMed  Google Scholar 

  • Skurkovich B, Skurkovich S (2006) Inhibition of IFN-gamma as a method of treatment of various autoimmune diseases, including skin diseases. Ernst Schering Res Found Workshop 56:1–27

    Article  PubMed  Google Scholar 

  • Solichova D, Melichar B et al (2001) Biochemical profile and survival in nonagenarians. Clin Biochem 34:563–569

    Article  CAS  PubMed  Google Scholar 

  • Sono M, Cady SG (1989) Enzyme kinetic and spectroscopic studies of inhibitor and effector interactions with indoleamine 2,3-dioxygenase. 1. Norharman and 4-phenylimidazole binding to the enzyme as inhibitors and heme ligands. Biochemistry 28:5392–5399

    Article  CAS  PubMed  Google Scholar 

  • Stewart JC et al (2007) Negative emotions and 3-year progression of subclinical atherosclerosis. Arch Gen Psychiatry 64:225–233

    Article  PubMed  Google Scholar 

  • Sucher R, Schroecksnadel K et al (2010) Neopterin, a prognostic marker in human malignancies. Cancer Lett 287(1):13–22

    Article  CAS  PubMed  Google Scholar 

  • Sullivan DT, Bell LA, Paton DR, Sullivan MC (1980) Genetic and functional analysis of tryptophan transport in malpighian tubules of Drosophila. Biochem Genet 18:1109–1130

    Article  CAS  PubMed  Google Scholar 

  • Tucker KL, Mattei J et al (2010) The Boston Puerto Rican Health Study, a longitudinal cohort study on health disparities in Puerto Rican adults: challenges and opportunities. BMC Public Health 10:107

    Article  PubMed  Google Scholar 

  • Tucker KJ, Oxenkrug GF et al (2010) Neopterin, pyridoxal-5′-phosphate and insulin resistance in adult community dwellers of Puerto Rican origin. Ann N Y Acad Sci (submitted)

  • 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

    PubMed  Google Scholar 

  • Ursavaş A, Karadag M, Oral AY et al (2008) Association between serum neopterin, obesity and daytime sleepiness in patients with obstructive sleep apnea. Respir Med 102:1193–1197

    Article  PubMed  Google Scholar 

  • Voelker DR (2009) Genetic and biochemical analysis of non-vesicular lipid traffic. Annu Rev Biochem 78:827–856

    Article  CAS  PubMed  Google Scholar 

  • Walsh HA, Daya S (1997) Inhibition of hepatic tryptophan-2,3-dioxygenase: superior potency of melatonin over serotonin. J Pineal Res 23:20–23

    Article  CAS  PubMed  Google Scholar 

  • Weinstock JV, Elliott DE (2009) Helminths and the IBD hygiene hypothesis. Inflamm Bowel Dis 15:128–133

    Article  PubMed  Google Scholar 

  • Wirleitner B et al (2003) Immune activation and degradation of tryptophan in coronary heart disease. Eur J Clin Invest 33:550–554

    Article  CAS  PubMed  Google Scholar 

  • You T et al (2008) The metabolic syndrome is associated with circulating adipokines in older adults across a wide range of adiposity. J Gerontol A Biol Sci Med Sci 63:414–419

    PubMed  Google Scholar 

  • Zhang SD, Odenwald WF (1995) Misexpression of the white (w) gene triggers male-male courtship in Drosophila. Proc Natl Acad Sci USA 92:5525–5529

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This paper was supported by NIH MH083225.

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  1. Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University/Tufts Medical Center, Boston, MA, USA

    Gregory F. Oxenkrug

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  1. Gregory F. Oxenkrug
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Correspondence to Gregory F. Oxenkrug.

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Oxenkrug, G.F. Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders. J Neural Transm 118, 75–85 (2011). https://doi.org/10.1007/s00702-010-0475-7

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  • DOI: https://doi.org/10.1007/s00702-010-0475-7

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