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

Abstract

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.

Cerebrospinal Fluid Inflammatory Cytokine Levels in Patients With Major Psychiatric Disorders: A Multiplex Immunoassay Study

“…The bead-based Luminex® (Bio-Rad Laboratories, Inc.) platform has been used for CSF sample to measure 8 cytokine levels in 43 patients with BD or MDD ( Haroon et al, 2016 ), while the immunoassay-based protein array multiplex system has been used for CSF samples to measure 10 cytokine levels in 30 patients with BD and 30 controls ( Soderlund et al, 2011 ). The electro-chemiluminescence-based V-plex® (MesoScale Discovery) platform has also been used for CSF samples to measure 10 cytokine levels in 23 patients with chronic schizophrenia and 37 controls ( Schwieler et al, 2015 ), 5 cytokine levels in 11 patients with recent-onset schizophrenia and 12 controls ( Coughlin et al, 2016 ), 2 cytokine levels in 19 patients with current depression and 67 subjects without depression among older women ( Kern et al, 2014 ), and 11 cytokine levels in 16 patients with schizophrenia and 15 with affective disorders ( Maxeiner et al, 2014 ).…”

Beneficial effects of omega-3 fatty acid supplementation in schizophrenia: possible mechanisms

“…It has been shown that pro-inflammatory cytokines were increased in both serum and cerebrospinal fluid (CSF) in first-episode schizophrenia [163][164][165], and patients with chronic schizophrenia [166]. Postmortem studies have also shown inflammatory markers in the dorsolateral prefrontal cortex, and microglial activity and microglial cellular density were all increased in schizophrenic patients [165,[167][168][169]. The pro-inflammatory cytokines increase PLA2 activity and breakdown of membrane phospholipids in schizophrenic patients [38,170].…”

Decreased Serum Oxytocin and Increased Homocysteine in First-Episode Schizophrenia Patients

“…IL-6 has been suggested to mediate the microglial-induced inflammatory response to neurogenesis (17). Previous data showed higher serum and cerebrospinal fluid (CSF) IL-6 levels in SZ patients and increased mRNA expression of IL-6 in post-mortem brain of SZ patients (18–20). High sensitivity CRP (hsCRP) is a nonspecific marker of inflammatory state and is mainly synthesized by hepatocytes in response to proinflammatory cytokines.…”