CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: 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, K Saito, A H Miller, C L Raison, R Dantzer, K W Kelley, M A Lawson, B J Woolwine, G Vogt, J R Spivey, K Saito, A H Miller

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.

Figures

Figure 1. CSF Kynurenine, Quinolinic Acid, Kynurenic…
Figure 1. CSF Kynurenine, Quinolinic Acid, Kynurenic Acid and Tryptophan Concentrations in Control versus IFN-alpha/ribavirin-treated patients with HCV
Cerebrospinal fluid (CSF) samples were obtained from control (n=11) and interferon (IFN)-alpha/ribavirin-treated (n=14-16) patients with hepatitis C virus (HCV) infection. IFN-alpha/ribavirin-treated subjects were studied after ~12 weeks on IFN-alpha/ribavirin therapy. CSF concentrations of kynurenine (KYN), quinolinic acid (QUIN), and kynurenic acid (KA) were significantly elevated in IFN-alpha-treated subjects compared to controls. No differences between groups in CSF tryptophan (TRP) concentrations were found. *p

Figure 2. Correlation between CSF Quinolinic Acid…

Figure 2. Correlation between CSF Quinolinic Acid and Depression Scores in Control and IFN-alpha/ribavirin-treated patients…

Figure 2. Correlation between CSF Quinolinic Acid and Depression Scores in Control and IFN-alpha/ribavirin-treated patients with HCV
Cerebrospinal fluid (CSF) samples were obtained from control (n=11) and interferon (IFN)-alpha/ribavirin-treated (n=14) patients with hepatitis C virus (HCV) infection. IFN-alpha/ribavirin-treated subjects were studied after ~12 weeks on IFN-alpha/ribavirin therapy. Symptoms of depression were assessed using the Montgomery Asberg Depression Rating Scale (MADRS). CSF quinolinic acid (QUIN) significantly correlated with MADRS scores (Spearman's rho=0.47, df=23, p=0.019).

Figure 3. Plasma Kynurenine, Quinolinic Acid, and…

Figure 3. Plasma Kynurenine, Quinolinic Acid, and Tryptophan Concentrations and the Kynurenine to Tryptophan Ratio…

Figure 3. Plasma Kynurenine, Quinolinic Acid, and Tryptophan Concentrations and the Kynurenine to Tryptophan Ratio in Control versus IFN-alpha/ribavirin-treated patients with HCV
Plasma samples were obtained from control (n=11) and interferon (IFN)-alpha/ribavirin-treated (n=16) patients with hepatitis C virus (HCV) infection. IFN-alpha/ribavirin-treated subjects were studied after ~12 weeks on IFN-alpha/ribavirin therapy. Plasma concentrations of kynurenine (KYN) and the kynurenine to tryptophan (K/T) ratio were significantly elevated in IFN-alpha-treated subjects compared to controls, whereas plasma tryptophan (TRP) concentrations were significantly decreased in IFN-alpha-treated patients. Values are depicted as the Mean ± Standard Error of the Mean. QUIN-quinolinic acid; *p
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    1. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56. - PMC - PubMed
    1. Miller GE, Rohleder N, Cole SW. Chronic interpersonal stress predicts activation of pro- and anti-inflammatory signaling pathways 6 months later. Psychosom Med. 2009;71:57–62. - PMC - PubMed
    1. Anisman H, Merali Z, Hayley S. Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol. 2008;85:1–74. - PubMed
    1. Yirmiya R. Endotoxin produces a depressive-like episode in rats. Brain Res. 1996;711:163–174. - PubMed
    1. Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15:199–226. - PubMed
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Figure 2. Correlation between CSF Quinolinic Acid…
Figure 2. Correlation between CSF Quinolinic Acid and Depression Scores in Control and IFN-alpha/ribavirin-treated patients with HCV
Cerebrospinal fluid (CSF) samples were obtained from control (n=11) and interferon (IFN)-alpha/ribavirin-treated (n=14) patients with hepatitis C virus (HCV) infection. IFN-alpha/ribavirin-treated subjects were studied after ~12 weeks on IFN-alpha/ribavirin therapy. Symptoms of depression were assessed using the Montgomery Asberg Depression Rating Scale (MADRS). CSF quinolinic acid (QUIN) significantly correlated with MADRS scores (Spearman's rho=0.47, df=23, p=0.019).
Figure 3. Plasma Kynurenine, Quinolinic Acid, and…
Figure 3. Plasma Kynurenine, Quinolinic Acid, and Tryptophan Concentrations and the Kynurenine to Tryptophan Ratio in Control versus IFN-alpha/ribavirin-treated patients with HCV
Plasma samples were obtained from control (n=11) and interferon (IFN)-alpha/ribavirin-treated (n=16) patients with hepatitis C virus (HCV) infection. IFN-alpha/ribavirin-treated subjects were studied after ~12 weeks on IFN-alpha/ribavirin therapy. Plasma concentrations of kynurenine (KYN) and the kynurenine to tryptophan (K/T) ratio were significantly elevated in IFN-alpha-treated subjects compared to controls, whereas plasma tryptophan (TRP) concentrations were significantly decreased in IFN-alpha-treated patients. Values are depicted as the Mean ± Standard Error of the Mean. QUIN-quinolinic acid; *p

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