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CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: relationship to CNS immune responses and depression

Molecular Psychiatry volume 15, pages 393–403 (2010)Cite this article

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)-α. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-α 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 ∼12 weeks of either treatment with IFN-α (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery–Asberg Depression Rating Scale. IFN-α 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-α had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-α, soluble tumor necrosis factor-α receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-α activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.

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Acknowledgements

This study was supported by grants from the National Institutes of Health to CLR (K23 MH064619 and R01 MH070553), RD (R01 MH 71349 and R01 MH 079829), KWK (R01 AG 029573) and AHM (K05 MH069124 and R01 HL073921 and T32 MH020018) as well as the Centers for Disease Control and Prevention. In addition, this study was supported by PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program and PHS Grant M01 RR0039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources. We thank Philip Harvey, PhD, for his assistance with statistical analyses and Suwako Fujigaki for technical assistance with the assay for QUIN.

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  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    C L Raison, B J Woolwine, G Vogt & A H Miller

  2. Integrative Immunology and Behavior Program, University of Illinois Urbana-Champaign, Champaign, IL, USA

    R Dantzer, K W Kelley & M A Lawson

  3. Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

    J R Spivey

  4. Human Health Sciences, Kyoto University Graduate School of Medicine and Faculty of Medicine, Kyoto, Japan

    K Saito

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Raison, C., Dantzer, R., Kelley, K. et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: relationship to CNS immune responses and depression. Mol Psychiatry 15, 393–403 (2010). https://doi.org/10.1038/mp.2009.116

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