title: CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression.
abstract: Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-alpha has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after approximately 12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Raison
authors.forename: R
authors.initials: R
authors.lastname: Dantzer
authors.forename: K W
authors.initials: KW
authors.lastname: Kelley
authors.forename: M A
authors.initials: MA
authors.lastname: Lawson
authors.forename: B J
authors.initials: BJ
authors.lastname: Woolwine
authors.forename: G
authors.initials: G
authors.lastname: Vogt
authors.forename: J R
authors.initials: JR
authors.lastname: Spivey
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.forename: A H
authors.initials: AH
authors.lastname: Miller
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016207:Cytokines / Q000134:cerebrospinal fluid; D003863:Depression / Q000134:cerebrospinal fluid / Q000209:etiology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006526:Hepatitis C / Q000097:blood / Q000134:cerebrospinal fluid / Q000150:complications / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007737:Kynurenine / Q000097:blood / Q000134:cerebrospinal fluid*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017378:Quinolinic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000134:cerebrospinal fluid; D012254:Ribavirin / Q000627:therapeutic use; D013223:Statistics as Topic; D014364:Tryptophan / Q000097:blood / Q000134:cerebrospinal fluid*
chemical_list: D000998:Antiviral Agents; D018932:Chemokine CCL2; D016207:Cytokines; D016898:Interferon-alpha; D047889:Receptors, Tumor Necrosis Factor, Type II; D007737:Kynurenine; D012254:Ribavirin; D014364:Tryptophan; D017378:Quinolinic Acid