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.

Fig. 1

Interferon-gamma (+874) and pteridines and kynurenine metabolic pathways. IFNG interferon-gamma, GTP guanosine triphosphate, GTPCH GTP cyclohydrolase, NEO neopterin, BH4 tetrahydrobiopterin, ARG arginine, NO nitric oxide, NOS nitric oxide synthase, TRY tryptophan, IDO indoleamine 2,3-dioxygenase, $O_2^{-}$ superoxide anion, PA picolinic acid, QA quinolinic acid

Fig. 2

Major derivatives of tryptophan–kynurenine metabolism. TRY tryptophan, ABC ATP-binding cassette drug transporter, NAS N-acetylserotonin, IDO indoleamine 2,3-dioxygenase, NAD nicotinamide adenine dinucleotide

Fig. 3

Interferon-gamma and guanine–BH4 pathway. ABC ATP-binding cassette transporter, IFNG interferon-gamma, TNF-alpha tumor necrosis factor-alpha, GTP guanosine triphosphate, GTPCH GTPcyclohydrolase 1, BH2 7,8-dihydroneopterin, PTPS pyruvoyl tetrahydropterin synthase, BH4 tetrahydrobiopterin, NOS nitric oxide synthase

Fig. 4

IDO/GTPCH upregulation and AAMPD. TRY tryptophan, IDO indoleamine 2,3-dioxygenase, BBB blood brain barrier, GTP guanosine triphosphate, KYN kynurenine, 3HK 3-hydroxyKYN, KYNA kynurenic acid, QA quinolinic acid, PA picolinic acid, NO nitric oxide, NOS NO synthase, PLA phospholipase 2, AA arachidonic acid, COX cyclooxygenase, 5-LO arachidonate 5-lipoxygenase, PGE prostaglandins

Fig. 5

IFNG-inducible KYNs/pteridines inflammation cascade. ABC ATP-binding cassette transporter, IFNG interferon-gamma, TNF-alpha tumor necrosis factor-alpha, TRY tryptophan, IDO indoleamine 2,3-dioxygenase, KYN kynurenine, XA xanthurenic acid, QA quinolinic acid, PA picolinic acid, GTP guanosine triphosphate, GTPCH GTPcyclohydrolase, BH4 tetrahydrobiopterin, NO nitric oxide, NOS NO synthase, $O_2^{-}$ superoxide anion

Fig. 6

Xanthurenic acid and insulin resistance. IFNG interferon-gamma, TNF-alpha tumor necrosis factor-alpha, XA xanthurenic acid, In insulin, Zn zink

Fig. 7

Shift of post-KYN metabolism toward formation of XA in vitamin B6 deficiency. IDO indoleamine 2,3,-dioxygenase, KYN kynurenine, 3OHKYN 3-hydroxyKYN, QUIN quinolinic acid, PICA picolinic acid, XA xanthurenic acid, NOS nitric oxide synthase