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

摘要

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.