Lowered paraoxonase 1 (PON1) activity is associated with increased cytokine levels in drug naïve first episode psychosis
Introduction
Schizophrenia is a severe and debilitating psychiatric disorder. However, its etiology and pathophysiology remains elusive. Many lines of evidence support the hypothesis that immune-inflammatory pathways are involved in the pathophysiology of schizophrenia (Anderson et al., 2013). Based on findings that monocytic and T-lymphocytic cytokines are increased in schizophrenia, Smith and Maes proposed the macrophage-T-lymphocyte theory of schizophrenia (Smith and Maes, 1995). Schwarz et al. proposed the T-helper 2 (Th2) hypothesis, which argues that a shift from T-helper 1 (Th1) cell immune function towards Th2 cells would occur during the disorder (Schwarz et al., 2001). In a meta-analysis, significant alterations in the cytokine network were described, suggesting that interleukin (IL)-1β, IL-6 and transforming growth factor (TGF)-β are state-related markers, as they are increased during the acute phase of psychosis and normalized with treatment (Miller et al., 2011). On the other hand, IL-12, interferon (INF)-γ, tumor necrosis factor (TNF)-α and soluble receptors for IL-2 seems to be trait markers (Miller et al., 2011). The same meta-analysis found significantly higher levels of IL-1β, IL-6, IL-12, IFN-γ, TNF-α, TGF-β and sIL-2R when considering the few studies performed on drug-naïve first episode psychosis (FEP) patients. A more recent meta-analysis conducted with studies that investigated cytokine levels (and their soluble receptors) in the serum of FEP reported higher levels of IL-1β, sIL-2R, IL-6 and TNF-α (Upthegrove et al., 2014). This profile suggests macrophage 1 (M1) and Th1 activation during the onset of the disorder in accordance with the Smith and Maes hypothesis (Smith and Maes, 1995). We recently reported a cytokine imbalance in drug-naïve FEP patients, with increased levels of IL-6, IL-10 and TNF-α, indicating monocytic and T regulatory cell (Treg) activation (Noto et al., 2015). We also demonstrated that treatment with the antipsychotic risperidone has immunoregulatory effects, normalizing the initial disturbance in monocytic, Th2 and Treg functions (Noto et al., 2014).
Activation of immune-inflammatory pathways is associated with oxidative stress and damage to lipids, DNA and proteins (Moylan et al., 2014). Chronic inflammatory conditions are associated with a decrease in antioxidant defenses and increased production of reactive oxygen species (ROS) (Moylan et al., 2014). Due to increased demand in situations of overwhelming ROS production, for example, by activated immune effector cells (e.g. macrophages), patients often show low blood levels of antioxidants (Monji et al., 2009) and enhanced oxidative stress markers (Arion et al., 2007). Oxidative stress (OS) is the result of an increased production of ROS and/or a reduction of anti-oxidant defenses. Increased neuronal OS causes damage to membrane phospholipids, induced by peroxidation and direct damage to proteins and genes. This pathway affects signal transduction, structural plasticity and cellular resilience and is therefore related to putatively neuroprogressive disorders, such as schizophrenia (Dietrich-Muszalska and Kontek, 2010, Fenton et al., 2000).
Paraoxonase 1 (PON1) is a plasmatic enzyme, mostly bound to high-density lipoprotein (HDL) particles, that has antioxidant and anti-inflammatory activities (Aviram and Rosenblat, 2004). An inverse relationship between PON1 activity and inflammatory responses has been described in numerous experimental models and clinical conditions, such as cardiovascular disease (Mackness et al., 2002), diabetes (Mackness et al., 2004), hypercholesterolemia (Zhu et al., 2014), ulcerative colitis (Boehm et al., 2009), Crohn’s disease (Boehm et al., 2009), parasite infection (Farid et al., 2010) and psoriasis (Bacchetti et al., 2013).
In medicated patients with schizophrenia, PON1 activity is lower than in healthy controls (Mabrouk et al., 2014, Unsal et al., 2013). However, since patients were taking antipsychotic drugs, the effects of medication on PON1 activity could have influenced these results. There is also some evidence that depression is accompanied by lowered PON1 activity (Bortolasci et al., 2014).
The aim of this study was to compare serum arylesterase PON1 activity and the levels of pro-inflammatory cytokines in drug-naïve first episode psychosis patients (FEP) and a healthy control group, and evaluate the relationship between PON1 activity and the levels of cytokines in drug-naïve FEP patients. The hypothesis was to find an inverse relationship between lowered PON1 activity and increased cytokine levels in FEP and that this inverse association is mediated by the presence of depression in FEP patients. To our knowledge, this is the first study aiming to investigate the relation of PON1 and cytokines in psychotic disorders.
Section snippets
Subjects and methods
This study is part of a prospective cohort performed in Sao Paulo, Brazil, that combines the assessment of different characteristics of drug-naïve FEP patients, immune-inflammatory assessment and levels of PON1. The results of the cytokine profile have been published elsewhere (Noto et al., 2014, Noto et al., 2015). The study was carried out in accordance with the Declaration of Helsinki and was approved by The Research Ethics Committee of UNIFESP (Sao Paulo, Brazil). All participants provided
Subjects
In the current study, fifty-one acute drug naïve FEP patients were recruited from an emergency unit. The diagnosis was made by trained psychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR), using the Structured Clinical Interview of the DSM-IV-TR (SCID-I). The mean duration of untreated psychosis (DUP) was 250 days (SD: 442). DUP was defined as the time between the onset of the first psychotic symptom and the hospital admission. All
Measurements
A blood sample of 10 mL was withdrawn from all individuals. Blood was immediately centrifuged, and the serum was aliquoted and stored at − 80 °C until thawed for the assays of the biomarkers. Total serum activity of PON1 was determined by the method described by Richter, Jarvik and Furlong (Richter et al., 2008). The rate of hydrolysis of phenyl acetate was determined in a microplate reader EnSpire, Perkin Elmer® (Waltham, MA, USA) at 270 nm and the temperature maintained at 25 °C. Measures were
Statistical analysis
Differences in sociodemographic and clinical characteristics between FEP patients and controls were assessed using analyses of variance (ANOVAs) and analyses of contingency tables (χ2 tests) or Fisher’s exact probability test. Multivariate general linear model (GLM) analyses were used to examine the effects of explanatory variables, including PON1 activity, diagnosis (FEP versus controls), age and sex, on the levels of the four cytokines. We also examined the effects of three study groups
Results
Table 1 shows the sociodemographic data and measurements of the cytokines and PON1 levels in the controls and FEP patients. There were no significant differences regarding age, sex or ethnicity between both study groups, while there were more current smokers in those with FEP than in controls. ANOVAs showed significantly increased IL-4, IL-10 and TNF-α values in FEP patients as compared to controls, whereas PON1 activity levels were significantly decreased in the FEP patients. There was a trend
Discussion
In the present study, FEP patients showed decreased serum PON1 arylesterase activity and increased IL-4, IL-10 and TNF-α levels as compared to healthy controls. Additionally, a significant inverse relationship between lowered serum PON1 activity and increased levels of IL-4, IL-6 and IL-10 were detected in FEP patients and controls combined (after controlling for the effects of diagnosis), showing that these relationships are present irrespective of diagnosis. We found that individuals with
Role of Funding
CN, KLB and CCF have received PhD scholarships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). VKO received PhD scholarship from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 2010/19176-3). LH has received master scholarships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). EB is supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), FAPESP and CAPES. SIB and RAB are supported by FAPESP (2010/08968-3
Contributors
C. Noto, V.K. Ota, A. Gadelha, R.A. Bressan, S.I. Belangero and E. Brietzke designed the study and wrote the protocol. C. Noto, A. Gadelha and Q. Cordeiro selected and interviewed the participants. F.F. Brinholi, K.L. Bonifácio, H.O. Vargas, L. Higachi, C.C. Farias, E.G. Moreira and D.S. Barbosa performed the experiments. F.F. Brinholi, C. Noto, M. Maes, H.O. Vargas, E.G. Moreira and D.S. Barbosa conducted the literature search, analyzed the data, and wrote the first draft of the manuscript.
Conflict of interest
Dr. Gadelha was on the Speakers’ Bureau and/or has acted as a consultant for Janssen-Cilag. Dr. Bressan has received research funding from FAPESP, CNPq, CAPES, Fundação Safra, Fundação ABADS, Janssen, Eli Lilly, Lundbeck, Novartis and Roche, has served as a speaker for Astra Zeneca, Bristol, Janssen, Lundbeck and Revista Brasileira de Psiquiatria, and is a shareholder of Radiopharmacus Ltda and Biomolecular Technology Ltda. The other authors have no conflicts of interest to disclose.
Acknowledgements
The authors are thankful to the patients, their families, and healthy volunteers.
References (37)
- et al.
A depression rating scale for schizophrenics
Schizophr. Res.
(1990) - et al.
Paraoxonase 1 (PON1) reduces macrophage inflammatory responses
Atherosclerosis
(2013) - et al.
Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2013) - et al.
Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia
Biol. Psychiatry
(2007) - et al.
Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development
Free Radic. Biol. Med.
(2004) - et al.
Lowered plasma paraoxonase (PON)1 activity is a trait marker of major depression and PON1 Q192R gene polymorphism-smoking interactions differentially predict the odds of major depression and bipolar disorder
J. Affect. Disord.
(2014) - et al.
Interleukin-6 upregulates paraoxonase 1 gene expression via an AKT/NF-kappaB-dependent pathway
Biochem. Biophys. Res. Commun.
(2013) - et al.
Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response
Atherosclerosis
(1998) - et al.
Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia
Biol. Psychiatry
(2000) - et al.
Human paraoxonase-1 gene expression by HepG2 cells is downregulated by interleukin-1beta and tumor necrosis factor-alpha, but is upregulated by interleukin-6
Life Sci.
(2003)
PON1 is a longevity gene: Results of a meta-analysis
Ageing Res. Rev.
Paraoxonase 1 activity and lipid profile in schizophrenic patients
Asian J. Psychiatry
Paraoxonase and coronary heart disease
Atheroscler. Suppl.
Paraoxonase-1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells
Biochem. Biophys. Res. Commun.
Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression
Cytokine
Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects
Biol. Psychiatry
Oxidative & nitrosative stress in depression: why so much stress?
Neurosci. Biobehav. Rev.
The Th2-hypothesis of schizophrenia: a strategy to identify a subgroup of schizophrenia caused by immune mechanisms
Med. Hypotheses
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Both authors contributed equally to this work.