Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity

Lindqvist, Daniel; Janelidze, Shorena; Hagell, Peter; Erhardt, Sophie; Samuelsson, Martin; Minthon, Lennart; Hansson, Oskar; Björkqvist, Maria; Träskman‐Bendz, Lil; Brundin, Lena

doi:10.1016/j.biopsych.2009.01.030

Cited by 454 publications

(338 citation statements)

References 43 publications

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“…34,35 Further, in euthymic patients with bipolar disorder or in suicide attempters with depression this cytokine is reduced or elevated, respect ively. 36,37 The presently observed increase in CSF IL 6 in pa tients with chronic schizophrenia is in agreement with results of previous studies analyzing this cytokine in plasma or CSF. 11,12,14,,15,38 However, in a recent study from our labora tory, CSF IL 6 levels were not altered in patients with first episode schizophrenia compared with healthy volunteers; 13 rather, in those patients CSF IL 1β was increased.…”

Section: Discussionsupporting

confidence: 91%

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

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188

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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: 91%

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

Self Cite

188

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“…[14][15][16] Although this discrepancy may relate to fluctuations of cytokines along with various states of the disease, the cytokine profile of the brain may also clearly differ from that of the periphery. 8,17,18 Supporting a central origin of the presently observed increased IL-1β concentration, a recent postmortem study demonstrated higher protein and mRNA levels of IL-1β in patients with bipolar disorder. 13 However, since peripheral cyto kines may access the brain through a damaged blood-brain barrier or through volume diffusion where the barrier is absent, such as in paraventricular organs, a tentative contribution of peripheral cytokines to the brain in bipolar disorder should not be disregarded.…”

Section: Discussionmentioning

confidence: 88%

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

Söderlund

Olsson

Samuelsson

et al. 2011

J Psychiatry Neurosci

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168

121

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Background:In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention.Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. Methods: We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar dis order type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system. Results: The mean interleukin (IL)-1β level (4.2 pg/mL, standard error of the mean [SEM] 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respect ively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1β (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). Limitations: All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. Conclusion: Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1β in bipolar disorder. In recent years, a role of the immune system in the pathogenesis of psychiatric diseases has gained increased attention. In this regard, many investigators have focused on cytokines, proteins that directly initiate and control immunological responses. We recently demonstrated a selective activation of brain interleukin (IL)-1β in schizophrenia, 2 a disease that appears similar to bipolar disorder with regard to symptomatology, treatment and risk genes. 3,4 Interestingly, a polymorphism in the promoter region of the IL1B gene has been suggested to comprise a shared genetic susceptibility for bipolar disorder and schizophrenia. 5 Indeed, bipolar disorder appears to be linked to inflammation, as indicated by genetic polymorphisms, gene expression and cytokine activation, 6 although direct evidence for a pathophysiological involvement of the immune system of the brain is still sparse. This may be 115 related to the fact that evaluation of cytokine levels in patients with bipolar disorder has been restricted to serum analyses. The bidirectional communication between the immune system of the brain and that of peripheral organs is complex, 7 and serum cytokines do not predict brain cytokine activation in healthy volunteers. 8 Hence, the immune system of the brain, including local cytokine release from microglia and astrocytes, may be independent of the immune sys...

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“…These findings are consistent with observed decreased levels of IL-6 and its soluble receptor in the CSF of geriatric patients with major depression (Stübner et al, 1999). However, in contrast, one study showed a positive correlation between CSF IL-6 levels and depressive symptoms, and suicidal behavior (Lindqvist et al, 2009), whereas another study of patients with unipolar MDD determined that there were no differences in IL-6 levels between healthy controls and depressed patients (Carpenter et al, 2004). Finally, a longitudinal study of older women over a decade of intermittent psychiatric evaluations showed that low CSF IL-6 concentrations predicted the emergence of depressive symptoms (Kern et al, 2013).…”

Section: Csf Cytokines and Chemokines In Depressionmentioning

confidence: 99%

A review of the relationship between proinflammatory cytokines and major depressive disorder

Young

Bruno

Pomara

2014

Journal of Affective Disorders

360

228

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Cite this article as: Juan Young, Davide Bruno, Nunzio Pomara, A review of the relationship between proinflammatory Cytokines and major depressive disorder, Journal of Affective Disorders, http://dx.doi.org/10. 1016/j.jad.2014.07.032 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity

Cited by 454 publications

References 43 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

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

A review of the relationship between proinflammatory cytokines and major depressive disorder

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