Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia

Miller, Christine L.; Llenos, Ida C.; Dulay, Jeanette R; Barillo, Meliza M; Yolken, Robert H.; Weis, Serge

doi:10.1016/j.nbd.2003.12.015

Cited by 207 publications

(161 citation statements)

References 59 publications

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“…Indeed, increased TDO activity in the postmortem brains of patients with schizophrenia has been reported. 22,43 In line with this, the present study shows that fetal human cortical astrocytes respond to application of IL 6 with an in creased KYNA synthesis, suggesting an intimate interplay between IL 6 and the KYN pathway.…”

Section: Discussionsupporting

confidence: 87%

“…Thus, experimental studies demonstrate that elevated KYNA affects brain glutamatergic/dopaminergic neurotransmission, hereby im plicating activation of the KYN pathway in established mod els of schizophrenia. 18,43,44 Moreover, elevated KYNA induces schizophrenia like behaviour, such as disrupted prepulse in hibition 45 and auditory sensory gating 46 as well as impaired contextual discriminations, 47 spatial working memory 48,49 and attentional set shifting, 50 in rodents. Notably, a specific inhib itor of KYN aminotransferase II, which reduces brain KYNA levels, prevents ketamine induced working memory impair ments and tends to attenuate hallucinatory like behaviours in primates.…”

Section: Discussionmentioning

confidence: 99%

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Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Schwieler

Larsson

Skogh

et al. 2015

jpn

176

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IntroductionThe role of immune activation in schizophrenia has received increasing interest in recent years. Epidemiological studies have shown that infections and autoimmune diseases are clin ic ally important risk factors for the development of schizo phrenia. [1][2][3] Furthermore, a recent study integrating results from a meta analysis of genome wide association studies in schizophrenia found that the most significant changes were observed in genetic loci related to the immune system. 4 Also, patients with schizophrenia show microglial activation, as re vealed by positron emission tomography. 5,6 Further, postmor tem studies using messenger RNA (mRNA) expression or im munohistochemical detection have shown increased levels of immune related compounds. 7-9 A number of investigations have focused on cytokines, but these studies have not yielded a unanimous picture, possibly because of a number of con founding factors, such as smoking and dietary habits, body mass index (BMI), type and duration of antipsychotic treat ment and drug abuse -all factors potentially affecting the Background: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. Methods: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were ana lyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. Results: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. Limitations: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. Conclusion: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-d-aspartate receptor antagonist KYNA in patients with schizophrenia.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Schwieler

Larsson

Skogh

et al. 2015

jpn

176

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“…2b-d). As described previously 8 , healthy human brain showed only weak TDO staining in neurons (Fig. 1e).…”

Section: Tdo Degrades Trp To Kyn In Human Brain Tumourssupporting

confidence: 81%

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Opitz

Litzenburger

Sahm

et al. 2011

Nature

1,532

1,534

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“…TDO is expressed in the cytoplasm of neurons, astrocytes, and endothelial cells but not in microglia using immunohistochemistry on sections from human frontal cortex (Miller et al, 2004(Miller et al, , 2006. We extended these data by showing that human MAP2-positive primary neurons express TDO in their cytoplasm.…”

Section: Discussionmentioning

confidence: 58%

Characterization of the Kynurenine Pathway in Human Neurons

et al. 2007

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The kynurenine pathway is a major route of L-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.

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Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia

Cited by 207 publications

References 59 publications

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Characterization of the Kynurenine Pathway in Human Neurons

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