J Psychiatry Neurosci 2015;40(2):126-133
Lilly Schwieler, PhD*; Markus K. Larsson, MSc*; Elisabeth Skogh, MD; Magdalena E. Kegel, MSc; Funda Orhan, MSc; Sally Abdelmoaty, PhD; Anja Finn, MSc; Maria Bhat, BSc; Martin Samuelsson, MD, PhD; Kristina Lundberg, MD; Marja-Liisa Dahl, MD, PhD; Carl Sellgren, MD, PhD; Ina Schuppe-Koistinen, PhD; Camilla I. Svensson, PhD; Sophie Erhardt, PhD; Göran Engberg, PhD
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.
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.
*These authors contributed equally to this work.
Submitted May 15, 2014; Revised Aug. 13, 2014; Accepted Sept. 3, 2014; Early-released Dec. 2, 2014.
Acknowledgements: This work was supported by grants from the Swedish Medical Research Council awarded to G. Engberg (2009– 3068, 2011–4789), S. Erhardt (2009–7053, 2013–2838), C. Svensson (2009–3068) and M.-L. Dahl (2008–2578, 2013–2592); the Swedish Brain foundation, Petrus och Augusta Hedlunds Stiftelse, Östergötland County Council; the AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science, the Karolinska Institutet (KID). The authors thank the patients and healthy volunteers for their participation and the health professionals who facilitated the work.
Affiliations: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (Schwieler, Larsson, Kegel, Orhan, Abdelmoaty, Finn, Svensson, Erhardt, Engberg); Department of Clinical and Experimental Medicine, Section of Psychiatry, Faculty of Health Sciences, Linköping University, Linköping, Sweden (Skogh, Samuelsson, Lundberg); AstraZeneca, Research & Development, Innovative Medicines, Personalised Healthcare & Biomarkers, Science for Life Laboratory, Solna, Sweden (Bhat, Schuppe-Koistinen); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Bhat, Schuppe-Koistinen); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden (Dahl); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Sellgren).
Competing interests and funding: None declared. The clinical research study was sponsored by Linköping University Hospital with an in-kind contribution to the sample analysis from AstraZeneca. AstraZeneca neither influenced nor sponsored the clinical research performed at Linköping University. These data arise from a sample collection, not from a prospective trial and are therefore not recorded in any clinical trial registry.
Contributors: L. Schwieler, M. Larsson, E. Skogh, C. Svensson, S. Erhardt and G. Engberg designed the study. L. Schwieler, M. Larsson, E. Skogh, M. Kegel, S. Abdelmoaty, M. Bhat, M. Samuelsson, M.-L. Dahl and S. Erhardt acquired the data, which L. Schwieler, M. Larsson, F. Orhan, A. Finn, C. Sellgren, I. Shuppe-Koistinen, C. Svensson, S. Erhardt and G. Engberg analyzed. L. Schwieler, M. Larsson, S. Erhardt and G. Engberg wrote the article, which all authors reviewed and approved for publication.
Correspondence to: G. Engberg, Department of Physiology and Pharmacology, Karolinska Institutet SE-171 77, Stockholm, Sweden; firstname.lastname@example.org