CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α

Relationship to CNS immune responses and depression

C. L. Raison, R. Dantzer, K. W. Kelley, M. A. Lawson, B. J. Woolwine, G. Vogt, J. R. Spivey, Kuniaki Saito, A. H. Miller

Research output: Contribution to journalArticle

359 Citations (Scopus)

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 (n16) or no treatment (n11). 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.

Original languageEnglish
Pages (from-to)393-403
Number of pages11
JournalMolecular Psychiatry
Volume15
Issue number4
DOIs
Publication statusPublished - 01-04-2010

Fingerprint

Kynurenine
Quinolinic Acid
Tryptophan
Interferons
Cerebrospinal Fluid
Kynurenic Acid
Depression
Brain
Indoleamine-Pyrrole 2,3,-Dioxygenase
Cytokines
Receptors, Tumor Necrosis Factor, Type II
Cytokine Receptors
Chemokine CCL2
Hepatitis C
Chemokines
Therapeutics
Central Nervous System

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Raison, C. L. ; Dantzer, R. ; Kelley, K. W. ; Lawson, M. A. ; Woolwine, B. J. ; Vogt, G. ; Spivey, J. R. ; Saito, Kuniaki ; Miller, A. H. / CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α : Relationship to CNS immune responses and depression. In: Molecular Psychiatry. 2010 ; Vol. 15, No. 4. pp. 393-403.
@article{2eef49d27b7f4ac3802b8eb9e72668c3,
title = "CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: 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)-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 (n16) or no treatment (n11). 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.",
author = "Raison, {C. L.} and R. Dantzer and Kelley, {K. W.} and Lawson, {M. A.} and Woolwine, {B. J.} and G. Vogt and Spivey, {J. R.} and Kuniaki Saito and Miller, {A. H.}",
year = "2010",
month = "4",
day = "1",
doi = "10.1038/mp.2009.116",
language = "English",
volume = "15",
pages = "393--403",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "4",

}

CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α : Relationship to CNS immune responses and depression. / Raison, C. L.; Dantzer, R.; Kelley, K. W.; Lawson, M. A.; Woolwine, B. J.; Vogt, G.; Spivey, J. R.; Saito, Kuniaki; Miller, A. H.

In: Molecular Psychiatry, Vol. 15, No. 4, 01.04.2010, p. 393-403.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α

T2 - Relationship to CNS immune responses and depression

AU - Raison, C. L.

AU - Dantzer, R.

AU - Kelley, K. W.

AU - Lawson, M. A.

AU - Woolwine, B. J.

AU - Vogt, G.

AU - Spivey, J. R.

AU - Saito, Kuniaki

AU - Miller, A. H.

PY - 2010/4/1

Y1 - 2010/4/1

N2 - 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 (n16) or no treatment (n11). 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.

AB - 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 (n16) or no treatment (n11). 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.

UR - http://www.scopus.com/inward/record.url?scp=77950022119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950022119&partnerID=8YFLogxK

U2 - 10.1038/mp.2009.116

DO - 10.1038/mp.2009.116

M3 - Article

VL - 15

SP - 393

EP - 403

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 4

ER -