title: Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia--significance for activation of the kynurenine pathway.
abstract: 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 analyzed 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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lilly
authors.initials: L
authors.lastname: Schwieler
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Larsson
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Psychiatry, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Skogh
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magdalena E
authors.initials: ME
authors.lastname: Kegel
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Funda
authors.initials: F
authors.lastname: Orhan
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sally
authors.initials: S
authors.lastname: Abdelmoaty
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Finn
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, Personalised Healthcare & Biomarkers, Science for Life Laboratory, Solna, Sweden, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Bhat
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Psychiatry, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Samuelsson
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Psychiatry, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lundberg
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Dahl
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carl
authors.initials: C
authors.lastname: Sellgren
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, Personalised Healthcare & Biomarkers, Science for Life Laboratory, Solna, Sweden, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Svensson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Engberg
mesh_terms: D000328:Adult; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000134:cerebrospinal fluid*; D016209:Interleukin-8 / Q000134:cerebrospinal fluid; D007736:Kynurenic Acid / Q000134:cerebrospinal fluid; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000134:cerebrospinal fluid*; D014364:Tryptophan / Q000134:cerebrospinal fluid; D055815:Young Adult
chemical_list: C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D007737:Kynurenine; D014364:Tryptophan; D007736:Kynurenic Acid