title: Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine.
abstract: Accumulating data suggest a causative link between immune stimulation, disturbed metabolism of tryptophan, and pathogenesis of bipolar disorder and schizophrenia. The goal of this study was to examine the production of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and the expression of kynurenine pathway enzymes involved in their synthesis and metabolism in cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals. The assessment was performed under basal conditions or following treatment with interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, or their combinations, in cells exposed to exogenous kynurenine. In both groups of patients, the baseline production of KYNA and 3-HK was increased, as compared to control subjects. Case-treatment analyses revealed significant interactions between bipolar case status and IL-1β, IL-6, IFN-γ + TNF-α, or IFN-γ + IL-1β, as well as between schizophrenia case status and IL-1β, IFN-γ + TNF-α, or IFN-γ + IL-1β, in terms of higher 3-HK. Noteworthy, no case-treatment interactions in terms of KYNA production were found. Observed changes did not appear to correlate with the expression of genes encoding kynurenine aminotransferases (KATs), kynureninase (KYNU) or kynurenine-3-monooxygenase (KMO). The single nucleotide polymorphisms (SNPs), rs1053230 and rs2275163, in KMO influenced KYNA levels yet did not explain the case-treatment discrepancies. In conclusion, our present findings indicate the utility of skin-derived fibroblasts for kynurenines research and support the concept of kynurenine pathway alterations in bipolar disorder and schizophrenia. The increase in ratio between neurotoxic 3-HK and neuroinhibitory/neuroprotective KYNA following exposure to cytokines may account for altered neurogenesis and structural abnormalities characteristic for both diseases.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Sweden.
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Johansson
authors.forename: Björn
authors.initials: B
authors.lastname: Owe-Larsson
authors.forename: Linnéa
authors.initials: L
authors.lastname: Asp
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kocki
authors.forename: Mats
authors.initials: M
authors.lastname: Adler
authors.forename: Jerker
authors.initials: J
authors.lastname: Hetta
authors.forename: Renee
authors.initials: R
authors.lastname: Gardner
authors.forename: Gabriella B S
authors.initials: GB
authors.lastname: Lundkvist
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Urbanska
authors.forename: Håkan
authors.initials: H
authors.lastname: Karlsson
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006801:Humans; D007736:Kynurenic Acid; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000473:pathology*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D016207:Cytokines; C005045:3-hydroxykynurenine; D007737:Kynurenine; D007736:Kynurenic Acid
keywords: Interferon-γ; Interleukin-1β; Kynureninase; Kynurenine aminotransferase; Kynurenine-3-monooxygenase; Tumor necrosis factor-α