title: Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.
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.
authors.affiliation: Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University/Tufts Medical Center, Boston, MA, USA. goxenkrug@tuftsmedicalcenter.org
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Oxenkrug
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007737:Kynurenine / Q000378:metabolism / Q000502:physiology*; D001523:Mental Disorders / Q000235:genetics / Q000473:pathology*; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics; D011621:Pteridines / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011621:Pteridines; D007737:Kynurenine; D007371:Interferon-gamma
references.citation: Lancet. 1971 Jun 12;1(7711):1211-9
references.pmid: 4103080
references.citation: Ann N Y Acad Sci. 2005 Aug;1053:386-93
references.pmid: 16179544
references.citation: Ann Neurol. 1994 May;35(5):592-7
references.pmid: 7910004
references.citation: Ann N Y Acad Sci. 2010 Jun;1199:114-20
references.pmid: 20633116
references.citation: Life Sci. 1998;63(15):PL231-6
references.pmid: 9768878
references.citation: Oncogene. 2008 Oct 9;27(46):5975-87
references.pmid: 18711403
references.citation: J Am Coll Nutr. 2008 Jun;27(3):421-7
references.pmid: 18838531
references.citation: Free Radic Biol Med. 2000 Feb 15;28(4):615-24
references.pmid: 10719243
references.citation: Arch Gen Psychiatry. 2007 Nov;64(11):1333
references.pmid: 17984402
references.citation: Acta Vitaminol Enzymol. 1975;29(1-6):236-9
references.pmid: 1244098
references.citation: BMC Genet. 2009 Aug 14;10:45
references.pmid: 19682384
references.citation: Pediatr Infect Dis J. 2008 Apr;27(4):325-9
references.pmid: 18379373
references.citation: Mech Ageing Dev. 2009 Mar;130(3):179-88
references.pmid: 19071156
references.citation: Am J Clin Nutr. 2003 May;77(5):1112-8
references.pmid: 12716660
references.citation: Clin Chem Lab Med. 2006;44(3):317-21
references.pmid: 16519605
references.citation: J Nutr. 2010 Jan;140(1):103-10
references.pmid: 19906811
references.citation: J Neural Transm (Vienna). 2010 Jan;117(1):23-6
references.pmid: 19941150
references.citation: Synapse. 2006 Apr;59(5):290-8
references.pmid: 16416446
references.citation: Am J Psychiatry. 2010 May;167(5):580-8
references.pmid: 20123914
references.citation: Respir Med. 2008 Aug;102(8):1193-7
references.pmid: 18579365
references.citation: Exp Gerontol. 2002 Jan-Mar;37(2-3):315-9
references.pmid: 11772518
references.citation: J Pineal Res. 2007 Apr;42(3):272-9
references.pmid: 17349026
references.citation: J Interferon Cytokine Res. 2005 Jan;25(1):20-30
references.pmid: 15684619
references.citation: J Pineal Res. 1997 Aug;23(1):20-3
references.pmid: 9379342
references.citation: Biochem Genet. 1980 Dec;18(11-12):1109-30
references.pmid: 6788034
references.citation: Ann N Y Acad Sci. 2005 Aug;1053:334-47
references.pmid: 16179540
references.citation: Clin Chem. 2009 Jun;55(6):1135-46
references.pmid: 19395439
references.citation: Isr J Psychiatry Relat Sci. 2010;47(1):56-63
references.pmid: 20686200
references.citation: Scand J Immunol. 2005 Apr;61(4):387-90
references.pmid: 15853924
references.citation: Redox Rep. 2002;7(4):199-206
references.pmid: 12396664
references.citation: Curr Med Chem. 2009;16(35):4644-53
references.pmid: 19903144
references.citation: Arch Biochem Biophys. 1991 Dec;291(2):326-33
references.pmid: 1952947
references.citation: Clin Chem. 2002;48(4):643-5
references.pmid: 11901063
references.citation: Dialogues Clin Neurosci. 2009;11(3):319-32
references.pmid: 19877499
references.citation: Scand J Clin Lab Invest. 2008;68(8):767-70
references.pmid: 18622801
references.citation: Pharmacol Biochem Behav. 1982 Nov;17(5):939-44
references.pmid: 6184736
references.citation: Nephrol Dial Transplant. 2006 May;21(5):1317-22
references.pmid: 16410273
references.citation: Hypertens Res. 2007 Mar;30(3):259-67
references.pmid: 17510508
references.citation: Life Sci. 1996;58(21):1891-9
references.pmid: 8637415
references.citation: J Clin Psychiatry. 2010 Feb;71(2):138-49
references.pmid: 19895780
references.citation: J Chromatogr. 1991 Apr 19;565(1-2):436-40
references.pmid: 1874889
references.citation: J Clin Immunol. 1994 Nov;14(6):368-74
references.pmid: 7883864
references.citation: Circ Res. 2005 Feb 4;96(2):141-3
references.pmid: 15692091
references.citation: Blood. 2010 Feb 25;115(8):1632-9
references.pmid: 19897579
references.citation: BMC Public Health. 2010 Mar 01;10:107
references.pmid: 20193082
references.citation: Biochim Biophys Acta. 1999 Jul 15;1419(2):173-85
references.pmid: 10407069
references.citation: Neurochem Res. 1998 Oct;23(10):1297-302
references.pmid: 9804286
references.citation: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5525-9
references.pmid: 7777542
references.citation: Biomed Pharmacother. 2008 Jun;62(5):308-11
references.pmid: 18267354
references.citation: J Biol Chem. 1994 Mar 18;269(11):8128-33
references.pmid: 7510678
references.citation: Med Clin North Am. 2007 Nov;91(6):1063-77, viii
references.pmid: 17964909
references.citation: Hum Immunol. 2000 Sep;61(9):863-6
references.pmid: 11053629
references.citation: J Chromatogr. 1981 Sep 11;225(1):179-84
references.pmid: 6170650
references.citation: J Interferon Res. 1986 Dec;6(6):697-703
references.pmid: 3106526
references.citation: Clin Biochem. 2001 Oct;34(7):563-9
references.pmid: 11738393
references.citation: Cell Immunol. 1999 Aug 1;195(2):127-36
references.pmid: 10448012
references.citation: Circulation. 2007 Jun 19;115(24):3071-8
references.pmid: 17548728
references.citation: Mol Psychiatry. 2001 Nov;6(6):671-7
references.pmid: 11673795
references.citation: Annu Rev Biochem. 2009;78:827-56
references.pmid: 19489735
references.citation: Inflamm Bowel Dis. 2009 Jan;15(1):128-33
references.pmid: 18680198
references.citation: Eur J Endocrinol. 2006 May;154(5):691-7
references.pmid: 16645016
references.citation: Transplant Proc. 1998 Sep;30(6):2682-4
references.pmid: 9745547
references.citation: Ann N Y Acad Sci. 2007 Dec;1122:35-49
references.pmid: 18077563
references.citation: Menopause. 2001 Jul-Aug;8(4):266-73
references.pmid: 11449084
references.citation: Pathol Biol (Paris). 2006 Sep;54(7):375-86
references.pmid: 16904849
references.citation: Semin Nephrol. 2007 Jan;27(1):98-114
references.pmid: 17336692
references.citation: Eur J Clin Invest. 2003 Jul;33(7):550-4
references.pmid: 12814390
references.citation: Obes Surg. 2006 May;16(5):541-8
references.pmid: 16687019
references.citation: Ann N Y Acad Sci. 1999;890:155-66
references.pmid: 10668422
references.citation: Curr Drug Metab. 2002 Apr;3(2):203-9
references.pmid: 12003351
references.citation: Ernst Schering Res Found Workshop. 2006;(56):1-27
references.pmid: 16329644
references.citation: Cancer Lett. 2010 Jan 1;287(1):13-22
references.pmid: 19500901
references.citation: Brain Res. 1992 Aug 14;588(1):1-5
references.pmid: 1393560
references.citation: Arch Intern Med. 2008 Jul 28;168(14):1568-75
references.pmid: 18663170
references.citation: Adv Exp Med Biol. 1996;398:191-4
references.pmid: 8906265
references.citation: Clin Biochem. 2004 Aug;37(8):684-7
references.pmid: 15302611
references.citation: Neurosci Lett. 1988 Nov 22;94(1-2):145-50
references.pmid: 2468114
references.citation: Arch Gerontol Geriatr. 1992 Jul-Aug;15(1):13-9
references.pmid: 15374376
references.citation: Lancet. 1969 Jan 18;1(7586):132-6
references.pmid: 4178247
references.citation: J Leukoc Biol. 2000 Aug;68(2):260-6
references.pmid: 10947071
references.citation: Ann N Y Acad Sci. 2010 Jun;1199:1-14
references.pmid: 20633104
references.citation: Diabetes. 2007 Jan;56(1):72-9
references.pmid: 17192467
references.citation: Biochemistry. 1989 Jun 27;28(13):5392-9
references.pmid: 2789076
references.citation: J Cell Mol Med. 2010 Aug;14(8):2045-54
references.pmid: 20629991
references.citation: Exp Neurol. 2008 May;211(1):41-51
references.pmid: 18359018
references.citation: Mech Ageing Dev. 2000 May 18;115(1-2):1-20
references.pmid: 10854626
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2008 Oct 1;32(7):1758-9; author reply 1760
references.pmid: 18652869
references.citation: Neuroscience. 2006 Sep 15;141(4):1835-48
references.pmid: 16809003
references.citation: Curr Drug Metab. 2007 Apr;8(3):289-95
references.pmid: 17430117
references.citation: Clin Chim Acta. 1999 Apr;282(1-2):115-23
references.pmid: 10340439
references.citation: J Biochem. 1976 Apr;79(4):13P-21P
references.pmid: 931956
references.citation: Neurochem Res. 1980 Mar;5(3):223-39
references.pmid: 6154900
references.citation: Int J Neuropsychopharmacol. 2002 Dec;5(4):401-12
references.pmid: 12466038
references.citation: Br J Nutr. 1990 Jan;63(1):27-36
references.pmid: 2317476
references.citation: Int J Neuropsychopharmacol. 1998 Jul;1(1):35-40
references.pmid: 11281943
references.citation: Mech Ageing Dev. 2006 May;127(5):497-9
references.pmid: 16513157
references.citation: J Gerontol A Biol Sci Med Sci. 2008 Apr;63(4):414-9
references.pmid: 18426966
references.citation: J Clin Invest. 1964 Feb;43:228-36
references.pmid: 14162531
references.citation: J Pineal Res. 1998 May;24(4):215-8
references.pmid: 9572530
references.citation: Ann N Y Acad Sci. 2003 May;993:325-33; discussion 345-9
references.pmid: 12853324
references.citation: J Neural Transm (Vienna). 2011 Feb;118(2):271-4
references.pmid: 21161299
references.citation: Am J Neuroprot Neuroregen. 2011 Jun;3(1):48-52
references.pmid: 22308202
references.citation: Curr Neurovasc Res. 2005 Jul;2(3):249-60
references.pmid: 16181118
references.citation: Pharmacol Rep. 2006 Jul-Aug;58(4):507-11
references.pmid: 16963796
references.citation: Arch Gen Psychiatry. 2007 Feb;64(2):225-33
references.pmid: 17283290
references.citation: J Pharmacol Exp Ther. 2002 Oct;303(1):1-10
references.pmid: 12235226
references.citation: Sante. 2005 Jul-Sep;15(3):205-8
references.pmid: 16207585
references.citation: Acta Vitaminol Enzymol. 1984;6(3):221-8
references.pmid: 6524581
references.citation: Adv Exp Med Biol. 2003;527:121-5
references.pmid: 15206724
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):380-6
references.pmid: 17933448
references.citation: Bull Acad Natl Med. 2007 Apr-May;191(4-5):897-908; discussion 908-10
references.pmid: 18225444
references.citation: Int Immunopharmacol. 2006 Jun;6(6):903-7
references.pmid: 16644475
references.citation: Endocrinology. 2009 May;150(5):2161-8
references.pmid: 19179442
references.citation: Clin Exp Immunol. 2007 Apr;148(1):106-11
references.pmid: 17349013
references.citation: Am J Clin Nutr. 2010 Feb;91(2):337-42
references.pmid: 19955400
references.citation: J Biol Chem. 1992 Dec 5;267(34):24173-6
references.pmid: 1280257
references.citation: Vopr Med Khim. 1972;18(2):198-202
references.pmid: 4679586
references.citation: Verh K Acad Geneeskd Belg. 2008;70(3):193-219
references.pmid: 18669160
references.citation: Am J Hum Genet. 2009 Dec;85(6):833-46
references.pmid: 19944402
references.citation: Mol Endocrinol. 2010 Mar;24(3):657-66
references.pmid: 20150186
references.citation: Circ Res. 2008 Aug 29;103(5):467-76
references.pmid: 18658050
references.citation: Cell Mol Life Sci. 2010 Feb;67(3):353-68
references.pmid: 19826765