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TNF-related weak inducer of apoptosis (TWEAK) levels in schizophrenia
Psychiatry Research 229 (2015) 755–759
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TNF-related weak inducer of apoptosis (TWEAK) levels in schizophrenia Elif Tatlıdil Yaylacı a,n, Rabia Nazik Yüksel a, Kübranur Ünal b, Neslihan Altunsoy a, Merve Cingi a, Şafak Yalçın Şahiner a, Makbule Çiğdem Aydemir a, Erol Göka a a b
Ankara Numune Education and Research Hospital Psychiatry Department, Ankara, Turkey Ankara Numune Education and Research Hospital Biochemistry Department, Ankara, Turkey
art ic l e i nf o
a b s t r a c t
Article history: Received 5 February 2015 Received in revised form 14 July 2015 Accepted 5 August 2015 Available online 6 August 2015
Members of tumor necrosis factor (TNF) superfamily have roles in many biological events and pathogenesis of central nervous system (CNS) diseases. A relatively recently found member of this family, TNFrelated weak inducer of apoptosis (TWEAK) have importance both in development of pathological CNS processes and as a target for the treatment of these diseases. The aim of this study was to investigate whether TWEAK's plasma levels are different in patients with schizophrenia. For this purpose plasma TWEAK levels of 44 patients diagnosed with schizophrenia and control group of 40 healthy individuals were compared. Although numerical difference was found between TWEAK levels of patients and controls it was not statistically significant. When we tested for female and male patients and controls seperately, TWEAK levels of male patients were significantly lower than male controls. As far as we know this is the first study that investigates levels of TWEAK in patients with schizophrenia. Although we did not find statistically significant results in our study, we believe that difference could be found in future studies with higher number of subjects. Researches with non-studied TNF superfamily members like TWEAK and TNF-related apoptosis-inducing ligand (TRAIL) could contribute to the understanding of immune-cytokine related hypotheses of schizophrenia. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Tumor necrosis factor Cytokines Inflammation
1. Introduction Inflammation is the complex reaction of blood vessels against injury. This reaction includes the activation and recruitment of immune cells and increase in blood stream and vascular permeability (Miller et al., 2011). Usually, inflammation aims to protect and repair tissues (Goetz et al., 2004) but if inflammation is severe or continues for a prolonged duration, then it becomes toxic for tissues and causes chronic inflammatory and autoimmune diseases Brietzke and Kapczinski, 2008). There are vast amount of preclinical and clinical studies indicating that chronic inflammatory processes and immune mechanisms take part in the pathogenesis of schizophrenia (Smyth and Lawrie, 2013). Alterations in the peripheral members of immune system are reported widespreadly in patients with schizophrenia (Tomasik et al., 2014). Cytokines are some of the main molecules that mediate the interaction between peripheral immune system and central nervous system (Tian et al., 2014). n Correspondence to: Ankara Numune Education and Research Hospital Psychiatry Department, Ülkü Mah. Talatpaşa Bulv. No: 5, Altındağ, Ankara, Turkey. Fax: þ90 312 5085602. E-mail address: [email protected] (E. Tatlıdil Yaylacı).
http://dx.doi.org/10.1016/j.psychres.2015.08.006 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
Altered cytokine levels measured both in patients with schizophrenia and their first degree relatives suggest that immune system changes may be an endophenotype of the disorder (Nunes et al., 2006). There are various immune-cytokine related hypotheses suggested for pathogenesis of schizophrenia. While according to macrophage-T-lymphocyte theory proposed by Smith and Maes, IL-1, TNF, IFNα and IFNγ released by chronically activated macrophages and T-lymphocytes are the main mediators of schizophrenia (Smith and Maes, 1995), it was suggested in Th-2 hypothesis that antibody-dependent immune responses predominate in schizophrenia (Muller et al., 2000; Schwarz et al., 2001). Additionally different research groups found that proinflammatory cytokines and free radicals produced by activated macrophages in the central nervous system cause abnormal neurogenesis, neuronal degradation, and white matter abnormalities (Monji et al., 2009). In this model which is called microglia hypothesis, these abnormalities contribute to the pathophysiology of schizophrenia (Monji et al., 2009). CD4 þ T-helper lymphocytes have at least two subsets, Th1 and Th2. While the Th1 cells produce IFN-γ and activate cell-mediated immunity, Th2 cells produce IL-4, IL-5 and induce B-cells and activate eosinophil recruitment (Mosmann et al., 1986; Dong, 2006).
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It was suggested that schizophrenia could be related to an imbalance between Th1/Th2 cytokines and features a shift toward Th2 cell system (Muller et al., 2000). In the literature, studies on cytokine levels of schizophrenia patients have conflicting results. Potvin et al. showed an increase in in vivo levels of IL-1RA, IL-6, sIL-2R and a decrease in in vitro levels of IL-2 in schizophrenia patients (Potvin et al., 2008). In a thorough and much citated review made by Miller et al., these inconsistent results were summarized as follows: IL-1β, IL-6, TGFβ levels increase in acute episodes and return to normal levels so they could be proposed as state markers. IL-12, IFN-γ, TNF-α and sIL-2R levels increase in acute episodes and do not return to previous levels after anti-psychotic treatment so they could be proposed as trait markers (Miller et al., 2011). As TNF-α has effects on glutamate, serotonine and dopamine systems, it becomes an important area to study for the etiopathogenesis of schizophrenia (Yirmiya and Goshen, 2011; Galic et al., 2012; Tian et al., 2014). Results of those studies concerning the serum levels of TNF-α have been found to be inconsistent (Tian et al., 2014). While Francesconi et al. stated that TNF-α levels were lower in chronic schizophrenia patients than healthy controls (Francesconi et al., 2011), Lv et al. also confirmed this result and added that TNF-α levels were negatively correlated with Positive and Negative Syndrome Scale (PANSS) scores of the patients (Lv et al., 2014). Contradicting these results, majority of the studies reported elevated levels of TNF-α in patients with schizophrenia. In a study conducted with chronic schizophrenia patients, Naudin et al. showed that TNF-α levels of patients were higher than controls (Naudin et al., 1997) and similar studies came to the same conclusion with drug-naive first episode schizophrenia patients as well (Theodoropoulou et al., 2001). Additionally, some studies have failed to find any difference in TNF-α serum levels between drug-naïve patients with first-episode psychosis and healthy controls (Borovcanin et al., 2013) or chronic schizophrenia patients and healthy controls (Coelho et al., 2008). As an explanation of these different results, it was suggested that fluctuating nature of schizophrenia and the effect of anti-psychotic medications may change the detected levels of serum TNF-α (Tian et al., 2014). Up to this day, 19 ligands and 29 receptors were identified in the tumor necrosis factor superfamily (Aggarwal et al., 2012; Kumar et al., 2013). Members of this superfamily have roles in many biological events including immune system development and function (Wiley and Winkles, 2003) as well as in the pathogenesis of many central nervous system diseases such as multiple sclerosis and cerebral ischemia (Feuerstein et al., 1997; Juedes et al., 2000). A relatively recently found member of this family, TNF-related weak inducer of apoptosis (TWEAK), and its receptor fibroblast growth factor-inducible 14 (Fn14) are shown to have importance both in development of pathological processess and as a target for the treatment of these diseases (Yepes, 2007). TWEAK is a transmembrane glycoprotein with a C-terminal extracellular domain and a N-terminal intracellular domain. Its expression has been detected in brain, heart, skeletal and smooth muscle, pancreas, spleen and lymphocytes (Yepes, 2007). In addition, expression of its receptor Fn14 is found to be high on most tumor cell lines of non-lymphoid origin and low on fibroblasts and endothelial and epithelial cells of healthy tissue (Burkly et al., 2011; Wajant, 2013). Similar to the general properties of TNF family, TWEAK stimulates various cell lines in the proinflammatory pathways. As an example of this feature, TWEAK was shown to increase the severity of disease in rheumatoid arthritis by stimulating the expression of cytokines and adhesion molecules from synovial fibroblasts (Kamijo et al., 2008). In addition to its proinflammatory properties, another major
effect of TWEAK is on the vascular permeability including creating an increase in the permeability of blood brain barrier (Stephan et al., 2013). Both its proinflammatory and vascular permeability increasing effects add up to TWEAK's important role in cerebral ischemia. TWEAK causes cerebral tissue damage by increasing neuronal cell death, increasing the permeability of blood brain barrier and increasing the release of proinflammatory chemokines and cytokines by activating microglia and astrocytes (Haile et al., 2010). This blood brain barrier permeability increasing effect of TWEAK also contributes to the etiopathology of neuropsychiatric lupus (Stock et al., 2013) and multiple sclerosis (Stephan et al., 2013). In the light of those studies that established TWEAK's proinflammatory and vascular permeability increasing actions, we hypothesized that, as a relatively less known and less studied TNF superfamily member, TWEAK's plasma levels might be elevated or reduced in patients with schizophrenia. To test that hypothesis, the aim of the present study was to compare the TWEAK levels between patients with schizophrenia and healthy individuals and to investigate whether TWEAK levels are different between schizophrenia patients in acute episode and remission period.
2. Methods 2.1. Sample 53 Consecutive patients who were either admitted to our inpatient unit or came to our outpatient clinic for their regular follow-up assessments between October 2014-November 2014 and met the DSM-V diagnostic criteria for schizophrenia were evaluated. Of these patients 3 did not accept to participate in the study, 6 patients were excluded as they had medical illnesses and 3 patients were excluded because of obesity. 44 Patients (23 men, 21 women) and 40 age and gender matched controls (21 men, 19 women) were recruited for the study. The control group consisted of 40 healthy staff members of our hospital without any prior psychiatric diognosis or treatment history and current psychiatric complaints. Those control subjects were assessed by the same trained physician with the Turkish version of structured clinical interview for DSM-IV axis I disorders (First et al., 1996; Çorapçıoğlu et al., 1999). Exclusion criteria was to have obesity, diabetes mellitus, hypertension, cardiovascular disease, chronic inflammatuary disease and/or severe or unstable medical illnesses and other Axis I disorders. All subjects were medically healthy, as determined by physical and neurological examination and laboratory tests. Patients with schizophrenia were 16 outpatients in remission period who were all using antipsychotic medication and 28 inpatients with acute psychotic episode. Twenty-eight patients (12 inpatients and 16 outpatients) were using anti-psychotic medication of which 2 were typical, 25 were atypical and 1 was combination of typical and atypical anti-psychotics. Positive and Negative Syndrome Scale (PANSS) was also applied to assess the psychopathological status of patients (Kay et al., 1987; Kostakoğlu et al., 1999). 2.2. Procedure The required permission to conduct the study was taken from the local ethical comission of Ankara Numune Education and Research Hospital. Informed consent form was signed by patients in remission period and also by at least one first degree relative of patients in acute episode. Blood samples from patients and controls were collected between 9 am and 10 am after at least 8 h of starvation. Samples were rotated in centrifuge with 4000 rotations for 10 min and kept at 80 °C until thawed for assay. Soluable TWEAK concentrations were determined in duplicate, by eBiocience Instant ELISA kit (Ref: BMS2006, Lot: 93908035). Plasma TWEAK levels were recorded in pg/ml. The cost of blood level measurements was covered by our hospital's Investigation Budget Fund. 2.3. Statistical analysis SPSS 20.0 was used in the analysis of the data. Variables were tested for normality of distribution by means of the Kolmogorov–Smirnov test. Chi-square test, Student’s t-test and One-way ANOVA were performed, when appropriate, to compare demographic characteristics and cytokine levels of groups. All results are two-tailed, statistical significance was defined as p o 0.05.
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3. Results
Table 2 Comparison of TWEAK levels in inpatients, outpatients and healthy controls.
Mean age (36.02 710.56/32.147 8.50) and gender ratio (F/M 21/23 and 19/21) were similar between patients and healthy individuals (t¼1.83, p ¼ 0.71, df¼82 and χ² ¼0.98, p ¼0.58, df¼ 1 respectively). Mean PANSS score was 74.31 712.56 in the patient group. Mean TWEAK levels were 588.45 711.08 and 604.8 79.61 for patients with schizophrenia and for control subjects respectively. TWEAK plasma levels did not reveal a statistically significant difference between two groups (t ¼ 1.12, p 40.05, df ¼82) (Table 1) Mean PANSS score was 96.11 718.03 for inpatients and 45.81 78.86 for outpatients. When we compared TWEAK levels among inpatient group, outpatient group and control group the results were 582.90 7 15.94, 591.61 715.01 and 604.83 79.61 respectively. Although numerical differences between three groups were observed, no statistical significance could be established. (F¼ 0.69, p 40.05, df¼2;81) (Table 2). There was not any relationship between PANSS scores of patients and TWEAK levels as well (R ¼0.09, p ¼0.57, df ¼42) We tested levels of TWEAK for female and male patients and female and male controls seperately, again no difference could be found between female patients and female controls (591.83 712.74 and 605.59 719.26) (t ¼ 0.6, p 40.05, df¼38) but TWEAK levels of male patients were significantly lower than male controls (572.79 711.29 and 606.83 714.02) (t ¼ 2.43, p¼ 0.02 df¼ 42) (Table 1). When we made multiple comparisons and compared male and female inpatients and outpatients seperately we did not find any difference between TWEAK levels of subgroups (Table 3). We could not compute whether there are differences in TWEAK levels between patients on typical antipsychotics versus atypical antipsychotics because there were only two patients that were on typical antipsychotic medication.
4. Discussion Levels of various proinflammatory cytokines and receptors have been found to be different from healthy controls both in autoimmune diseases and in the peripheral blood and cerebrospinal fluid of patients with schizophrenia (Anderson et al., 2013; Bechter, 2013). As a result, these findings indicate the presence of immuno-inflammatory abnormalities in patients with schizophrenia. TWEAK is a multifunctional cytokine that regulates inflammatory pathways by inducing multiple cellular responses depending on the cell type and its micro-environment (Burkly et al., 2007). It is now established that TWEAK plays a role in the pathophysiology of autoimmune and chronic diseases and the first clinical trials based on anti-TWEAK-blocking therapies are in progress for RA and SLE (Wisniacki et al., 2013). As far as we know this is the first study that investigates levels of TWEAK in patients with schizophrenia. TWEAK is a member of the TNF superfamily whose fundemental member is TNF-α. Table 1 Comparison of TWEAK levels in patients with schizophrenia and healthy controls, between male schizophrenia patients and male controls and female schizophrenia patients and female controls.
Male Female Total
757
Patients
Controls
Analysis (t, p)
572.79 711.29 591.83 712.74 588.45 711.08
606.837 14.02 605.59 7 19.26 604.807 9.61
2.43 0.02 0.60 0.56 1.12 0.27
Inpatients,n¼28
Outpatients,n¼ 16
Controls,n¼ 40
Analysis (F, p)
582.90 7 15.94
591.61 715.01
604.837 9.61
0.69 0.57
Table 3 Comparison of TWEAK levels in male and female inpatients and outpatients.
Male Female Total
Inpatients
Outpatients
Analysis (t, p)
565.93 7 14.59 584.90 7 32.20 582.90 7 15.941
581.707 18.21 595.96 7 24.01 591.617 15.011
0.68 0.51 0.22 0.85 0.40 0.70
Although there are numerous studies about TNF-α levels in schizophrenia patients, there are not any on relatively recently found members of this superfamily like TWEAK or TRAIL. In the only TWEAK study that was made in a psychiatric sample, Levandowski et al., found that TWEAK levels were lower in crack cocaine dependent women with early life stress than both crack cocaine dependent women without early life stress and healthy controls. They also stated that TWEAK levels were negatively associated with the severity of early life stress and severity of depression and also negatively correlated with TNF-α levels (Levandowski et al., 2014). In this study our patient group consisted of schizophrenia patients. When we investigated the TWEAK levels between patients with schizophrenia and healthy controls we could not find any difference with statistical significance. Then as the results of aforementioned TNF-α studies suggested TNF-α level differences between states of schizophrenia, we compared inpatient group who are in acute episode, outpatient group who are in remission period and healthy controls. Although we found visible differences between 3 groups, they again did not meet statistical significance. This may be because of relatively small study groups. Future studies with larger samples are needed to determine the relationship of TWEAK and states of schizophrenia. PANSS is a widely used scale that measures symptom severity and assesses change in symptoms over time in psychotic disorders. Several studies which investigated the correlation of TNF-α levels with PANSS scores before the initiation of antipsychotic medication and after remission was achieved did not find any relationship between the two (Kubistova et al., 2012; Ajami et al., 2014). Although we did not evaluated the same patients before and after treatment, our study sample consisted of both patients in acute episode and patients stable with medication. Thus, our results are congruent with the earlier TNF-α studies as we did not find any correlation between TWEAK levels and PANSS scores. There are studies which suggest that some antipsychotic drugs may have immunosuppressive effects and may alter cytokine levels (Song et al., 2000). As 28 out of 44 patients in our study group were using various kinds of anti-psychotic medications it would have been better if the study could have been conducted with a more homogenized patient sample in order to prevent the confounding effects of these drugs. Moreover, as there are some immunulogic evidence that indicate difference in cytokine levels between male and female genders (Jiang and Gilkeson, 2014; Moscovis et al., 2014), we investigated whether levels of TWEAK differ between male schizophrenia patients and male controls, and female schizophrenia patients and female controls. While we could not find any significant difference between female patients and female controls, TWEAK levels of male patients was significantly lower than healthy males. As we mentioned above, it may be suggested that if
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number of subjects had been higher, in addition to the statistically significant difference we found between male schizophrenia patients and male controls, these numerical differences between all other study groups could have achieved statistical significance as well.
5. Conclusion This is the first investigation about the levels of TWEAK in patients with schizophrenia. That is why we could not compare our results with other studies. Although we did not find statistically significant results in this novel study, we believe that difference could be found in future studies on TWEAK levels of patients with schizophrenia which are designed with higher number of subjects and focus on the difference between genders. In this respect, researches with non-studied TNF superfamily members like TWEAK and TRAIL could contribute to the understanding of immune-cytokine related hypotheses of schizophrenia. As mentioned above, the main limitation of this study was the comparatively small number of subjects that were recruited. The sample size is small, particularly when comparing those who are acutely ill with those who are stable. Another important limitation is the lack of taking into account of subjects' smoking and dietary habits which may affect cytokine levels. Although all patients and control subjects were in normal range of body mass index, it would be preferable if both groups were matched in regard to weight and tobacco use. Thirdly, the patients had been taking heterogeneous antipsychotics with various doses. Furthermore only one cytokine was assayed in this study sample at only one time point so its results are limited and should be reinvestigated in prospective studies.
Conflict of interest The authors declare no conflict of interest.
Acknowledgment No acknowledgment is present for the study.
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TNF-related weak inducer of apoptosis (TWEAK) levels in schizophrenia Elif Tatlıdil Yaylacı a,n, Rabia Nazik Yüksel a, Kübranur Ünal b, Neslihan Altunsoy a, Merve Cingi a, Şafak Yalçın Şahiner a, Makbule Çiğdem Aydemir a, Erol Göka a a b
Ankara Numune Education and Research Hospital Psychiatry Department, Ankara, Turkey Ankara Numune Education and Research Hospital Biochemistry Department, Ankara, Turkey
art ic l e i nf o
a b s t r a c t
Article history: Received 5 February 2015 Received in revised form 14 July 2015 Accepted 5 August 2015 Available online 6 August 2015
Members of tumor necrosis factor (TNF) superfamily have roles in many biological events and pathogenesis of central nervous system (CNS) diseases. A relatively recently found member of this family, TNFrelated weak inducer of apoptosis (TWEAK) have importance both in development of pathological CNS processes and as a target for the treatment of these diseases. The aim of this study was to investigate whether TWEAK's plasma levels are different in patients with schizophrenia. For this purpose plasma TWEAK levels of 44 patients diagnosed with schizophrenia and control group of 40 healthy individuals were compared. Although numerical difference was found between TWEAK levels of patients and controls it was not statistically significant. When we tested for female and male patients and controls seperately, TWEAK levels of male patients were significantly lower than male controls. As far as we know this is the first study that investigates levels of TWEAK in patients with schizophrenia. Although we did not find statistically significant results in our study, we believe that difference could be found in future studies with higher number of subjects. Researches with non-studied TNF superfamily members like TWEAK and TNF-related apoptosis-inducing ligand (TRAIL) could contribute to the understanding of immune-cytokine related hypotheses of schizophrenia. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Tumor necrosis factor Cytokines Inflammation
1. Introduction Inflammation is the complex reaction of blood vessels against injury. This reaction includes the activation and recruitment of immune cells and increase in blood stream and vascular permeability (Miller et al., 2011). Usually, inflammation aims to protect and repair tissues (Goetz et al., 2004) but if inflammation is severe or continues for a prolonged duration, then it becomes toxic for tissues and causes chronic inflammatory and autoimmune diseases Brietzke and Kapczinski, 2008). There are vast amount of preclinical and clinical studies indicating that chronic inflammatory processes and immune mechanisms take part in the pathogenesis of schizophrenia (Smyth and Lawrie, 2013). Alterations in the peripheral members of immune system are reported widespreadly in patients with schizophrenia (Tomasik et al., 2014). Cytokines are some of the main molecules that mediate the interaction between peripheral immune system and central nervous system (Tian et al., 2014). n Correspondence to: Ankara Numune Education and Research Hospital Psychiatry Department, Ülkü Mah. Talatpaşa Bulv. No: 5, Altındağ, Ankara, Turkey. Fax: þ90 312 5085602. E-mail address: [email protected] (E. Tatlıdil Yaylacı).
http://dx.doi.org/10.1016/j.psychres.2015.08.006 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
Altered cytokine levels measured both in patients with schizophrenia and their first degree relatives suggest that immune system changes may be an endophenotype of the disorder (Nunes et al., 2006). There are various immune-cytokine related hypotheses suggested for pathogenesis of schizophrenia. While according to macrophage-T-lymphocyte theory proposed by Smith and Maes, IL-1, TNF, IFNα and IFNγ released by chronically activated macrophages and T-lymphocytes are the main mediators of schizophrenia (Smith and Maes, 1995), it was suggested in Th-2 hypothesis that antibody-dependent immune responses predominate in schizophrenia (Muller et al., 2000; Schwarz et al., 2001). Additionally different research groups found that proinflammatory cytokines and free radicals produced by activated macrophages in the central nervous system cause abnormal neurogenesis, neuronal degradation, and white matter abnormalities (Monji et al., 2009). In this model which is called microglia hypothesis, these abnormalities contribute to the pathophysiology of schizophrenia (Monji et al., 2009). CD4 þ T-helper lymphocytes have at least two subsets, Th1 and Th2. While the Th1 cells produce IFN-γ and activate cell-mediated immunity, Th2 cells produce IL-4, IL-5 and induce B-cells and activate eosinophil recruitment (Mosmann et al., 1986; Dong, 2006).
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It was suggested that schizophrenia could be related to an imbalance between Th1/Th2 cytokines and features a shift toward Th2 cell system (Muller et al., 2000). In the literature, studies on cytokine levels of schizophrenia patients have conflicting results. Potvin et al. showed an increase in in vivo levels of IL-1RA, IL-6, sIL-2R and a decrease in in vitro levels of IL-2 in schizophrenia patients (Potvin et al., 2008). In a thorough and much citated review made by Miller et al., these inconsistent results were summarized as follows: IL-1β, IL-6, TGFβ levels increase in acute episodes and return to normal levels so they could be proposed as state markers. IL-12, IFN-γ, TNF-α and sIL-2R levels increase in acute episodes and do not return to previous levels after anti-psychotic treatment so they could be proposed as trait markers (Miller et al., 2011). As TNF-α has effects on glutamate, serotonine and dopamine systems, it becomes an important area to study for the etiopathogenesis of schizophrenia (Yirmiya and Goshen, 2011; Galic et al., 2012; Tian et al., 2014). Results of those studies concerning the serum levels of TNF-α have been found to be inconsistent (Tian et al., 2014). While Francesconi et al. stated that TNF-α levels were lower in chronic schizophrenia patients than healthy controls (Francesconi et al., 2011), Lv et al. also confirmed this result and added that TNF-α levels were negatively correlated with Positive and Negative Syndrome Scale (PANSS) scores of the patients (Lv et al., 2014). Contradicting these results, majority of the studies reported elevated levels of TNF-α in patients with schizophrenia. In a study conducted with chronic schizophrenia patients, Naudin et al. showed that TNF-α levels of patients were higher than controls (Naudin et al., 1997) and similar studies came to the same conclusion with drug-naive first episode schizophrenia patients as well (Theodoropoulou et al., 2001). Additionally, some studies have failed to find any difference in TNF-α serum levels between drug-naïve patients with first-episode psychosis and healthy controls (Borovcanin et al., 2013) or chronic schizophrenia patients and healthy controls (Coelho et al., 2008). As an explanation of these different results, it was suggested that fluctuating nature of schizophrenia and the effect of anti-psychotic medications may change the detected levels of serum TNF-α (Tian et al., 2014). Up to this day, 19 ligands and 29 receptors were identified in the tumor necrosis factor superfamily (Aggarwal et al., 2012; Kumar et al., 2013). Members of this superfamily have roles in many biological events including immune system development and function (Wiley and Winkles, 2003) as well as in the pathogenesis of many central nervous system diseases such as multiple sclerosis and cerebral ischemia (Feuerstein et al., 1997; Juedes et al., 2000). A relatively recently found member of this family, TNF-related weak inducer of apoptosis (TWEAK), and its receptor fibroblast growth factor-inducible 14 (Fn14) are shown to have importance both in development of pathological processess and as a target for the treatment of these diseases (Yepes, 2007). TWEAK is a transmembrane glycoprotein with a C-terminal extracellular domain and a N-terminal intracellular domain. Its expression has been detected in brain, heart, skeletal and smooth muscle, pancreas, spleen and lymphocytes (Yepes, 2007). In addition, expression of its receptor Fn14 is found to be high on most tumor cell lines of non-lymphoid origin and low on fibroblasts and endothelial and epithelial cells of healthy tissue (Burkly et al., 2011; Wajant, 2013). Similar to the general properties of TNF family, TWEAK stimulates various cell lines in the proinflammatory pathways. As an example of this feature, TWEAK was shown to increase the severity of disease in rheumatoid arthritis by stimulating the expression of cytokines and adhesion molecules from synovial fibroblasts (Kamijo et al., 2008). In addition to its proinflammatory properties, another major
effect of TWEAK is on the vascular permeability including creating an increase in the permeability of blood brain barrier (Stephan et al., 2013). Both its proinflammatory and vascular permeability increasing effects add up to TWEAK's important role in cerebral ischemia. TWEAK causes cerebral tissue damage by increasing neuronal cell death, increasing the permeability of blood brain barrier and increasing the release of proinflammatory chemokines and cytokines by activating microglia and astrocytes (Haile et al., 2010). This blood brain barrier permeability increasing effect of TWEAK also contributes to the etiopathology of neuropsychiatric lupus (Stock et al., 2013) and multiple sclerosis (Stephan et al., 2013). In the light of those studies that established TWEAK's proinflammatory and vascular permeability increasing actions, we hypothesized that, as a relatively less known and less studied TNF superfamily member, TWEAK's plasma levels might be elevated or reduced in patients with schizophrenia. To test that hypothesis, the aim of the present study was to compare the TWEAK levels between patients with schizophrenia and healthy individuals and to investigate whether TWEAK levels are different between schizophrenia patients in acute episode and remission period.
2. Methods 2.1. Sample 53 Consecutive patients who were either admitted to our inpatient unit or came to our outpatient clinic for their regular follow-up assessments between October 2014-November 2014 and met the DSM-V diagnostic criteria for schizophrenia were evaluated. Of these patients 3 did not accept to participate in the study, 6 patients were excluded as they had medical illnesses and 3 patients were excluded because of obesity. 44 Patients (23 men, 21 women) and 40 age and gender matched controls (21 men, 19 women) were recruited for the study. The control group consisted of 40 healthy staff members of our hospital without any prior psychiatric diognosis or treatment history and current psychiatric complaints. Those control subjects were assessed by the same trained physician with the Turkish version of structured clinical interview for DSM-IV axis I disorders (First et al., 1996; Çorapçıoğlu et al., 1999). Exclusion criteria was to have obesity, diabetes mellitus, hypertension, cardiovascular disease, chronic inflammatuary disease and/or severe or unstable medical illnesses and other Axis I disorders. All subjects were medically healthy, as determined by physical and neurological examination and laboratory tests. Patients with schizophrenia were 16 outpatients in remission period who were all using antipsychotic medication and 28 inpatients with acute psychotic episode. Twenty-eight patients (12 inpatients and 16 outpatients) were using anti-psychotic medication of which 2 were typical, 25 were atypical and 1 was combination of typical and atypical anti-psychotics. Positive and Negative Syndrome Scale (PANSS) was also applied to assess the psychopathological status of patients (Kay et al., 1987; Kostakoğlu et al., 1999). 2.2. Procedure The required permission to conduct the study was taken from the local ethical comission of Ankara Numune Education and Research Hospital. Informed consent form was signed by patients in remission period and also by at least one first degree relative of patients in acute episode. Blood samples from patients and controls were collected between 9 am and 10 am after at least 8 h of starvation. Samples were rotated in centrifuge with 4000 rotations for 10 min and kept at 80 °C until thawed for assay. Soluable TWEAK concentrations were determined in duplicate, by eBiocience Instant ELISA kit (Ref: BMS2006, Lot: 93908035). Plasma TWEAK levels were recorded in pg/ml. The cost of blood level measurements was covered by our hospital's Investigation Budget Fund. 2.3. Statistical analysis SPSS 20.0 was used in the analysis of the data. Variables were tested for normality of distribution by means of the Kolmogorov–Smirnov test. Chi-square test, Student’s t-test and One-way ANOVA were performed, when appropriate, to compare demographic characteristics and cytokine levels of groups. All results are two-tailed, statistical significance was defined as p o 0.05.
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3. Results
Table 2 Comparison of TWEAK levels in inpatients, outpatients and healthy controls.
Mean age (36.02 710.56/32.147 8.50) and gender ratio (F/M 21/23 and 19/21) were similar between patients and healthy individuals (t¼1.83, p ¼ 0.71, df¼82 and χ² ¼0.98, p ¼0.58, df¼ 1 respectively). Mean PANSS score was 74.31 712.56 in the patient group. Mean TWEAK levels were 588.45 711.08 and 604.8 79.61 for patients with schizophrenia and for control subjects respectively. TWEAK plasma levels did not reveal a statistically significant difference between two groups (t ¼ 1.12, p 40.05, df ¼82) (Table 1) Mean PANSS score was 96.11 718.03 for inpatients and 45.81 78.86 for outpatients. When we compared TWEAK levels among inpatient group, outpatient group and control group the results were 582.90 7 15.94, 591.61 715.01 and 604.83 79.61 respectively. Although numerical differences between three groups were observed, no statistical significance could be established. (F¼ 0.69, p 40.05, df¼2;81) (Table 2). There was not any relationship between PANSS scores of patients and TWEAK levels as well (R ¼0.09, p ¼0.57, df ¼42) We tested levels of TWEAK for female and male patients and female and male controls seperately, again no difference could be found between female patients and female controls (591.83 712.74 and 605.59 719.26) (t ¼ 0.6, p 40.05, df¼38) but TWEAK levels of male patients were significantly lower than male controls (572.79 711.29 and 606.83 714.02) (t ¼ 2.43, p¼ 0.02 df¼ 42) (Table 1). When we made multiple comparisons and compared male and female inpatients and outpatients seperately we did not find any difference between TWEAK levels of subgroups (Table 3). We could not compute whether there are differences in TWEAK levels between patients on typical antipsychotics versus atypical antipsychotics because there were only two patients that were on typical antipsychotic medication.
4. Discussion Levels of various proinflammatory cytokines and receptors have been found to be different from healthy controls both in autoimmune diseases and in the peripheral blood and cerebrospinal fluid of patients with schizophrenia (Anderson et al., 2013; Bechter, 2013). As a result, these findings indicate the presence of immuno-inflammatory abnormalities in patients with schizophrenia. TWEAK is a multifunctional cytokine that regulates inflammatory pathways by inducing multiple cellular responses depending on the cell type and its micro-environment (Burkly et al., 2007). It is now established that TWEAK plays a role in the pathophysiology of autoimmune and chronic diseases and the first clinical trials based on anti-TWEAK-blocking therapies are in progress for RA and SLE (Wisniacki et al., 2013). As far as we know this is the first study that investigates levels of TWEAK in patients with schizophrenia. TWEAK is a member of the TNF superfamily whose fundemental member is TNF-α. Table 1 Comparison of TWEAK levels in patients with schizophrenia and healthy controls, between male schizophrenia patients and male controls and female schizophrenia patients and female controls.
Male Female Total
757
Patients
Controls
Analysis (t, p)
572.79 711.29 591.83 712.74 588.45 711.08
606.837 14.02 605.59 7 19.26 604.807 9.61
2.43 0.02 0.60 0.56 1.12 0.27
Inpatients,n¼28
Outpatients,n¼ 16
Controls,n¼ 40
Analysis (F, p)
582.90 7 15.94
591.61 715.01
604.837 9.61
0.69 0.57
Table 3 Comparison of TWEAK levels in male and female inpatients and outpatients.
Male Female Total
Inpatients
Outpatients
Analysis (t, p)
565.93 7 14.59 584.90 7 32.20 582.90 7 15.941
581.707 18.21 595.96 7 24.01 591.617 15.011
0.68 0.51 0.22 0.85 0.40 0.70
Although there are numerous studies about TNF-α levels in schizophrenia patients, there are not any on relatively recently found members of this superfamily like TWEAK or TRAIL. In the only TWEAK study that was made in a psychiatric sample, Levandowski et al., found that TWEAK levels were lower in crack cocaine dependent women with early life stress than both crack cocaine dependent women without early life stress and healthy controls. They also stated that TWEAK levels were negatively associated with the severity of early life stress and severity of depression and also negatively correlated with TNF-α levels (Levandowski et al., 2014). In this study our patient group consisted of schizophrenia patients. When we investigated the TWEAK levels between patients with schizophrenia and healthy controls we could not find any difference with statistical significance. Then as the results of aforementioned TNF-α studies suggested TNF-α level differences between states of schizophrenia, we compared inpatient group who are in acute episode, outpatient group who are in remission period and healthy controls. Although we found visible differences between 3 groups, they again did not meet statistical significance. This may be because of relatively small study groups. Future studies with larger samples are needed to determine the relationship of TWEAK and states of schizophrenia. PANSS is a widely used scale that measures symptom severity and assesses change in symptoms over time in psychotic disorders. Several studies which investigated the correlation of TNF-α levels with PANSS scores before the initiation of antipsychotic medication and after remission was achieved did not find any relationship between the two (Kubistova et al., 2012; Ajami et al., 2014). Although we did not evaluated the same patients before and after treatment, our study sample consisted of both patients in acute episode and patients stable with medication. Thus, our results are congruent with the earlier TNF-α studies as we did not find any correlation between TWEAK levels and PANSS scores. There are studies which suggest that some antipsychotic drugs may have immunosuppressive effects and may alter cytokine levels (Song et al., 2000). As 28 out of 44 patients in our study group were using various kinds of anti-psychotic medications it would have been better if the study could have been conducted with a more homogenized patient sample in order to prevent the confounding effects of these drugs. Moreover, as there are some immunulogic evidence that indicate difference in cytokine levels between male and female genders (Jiang and Gilkeson, 2014; Moscovis et al., 2014), we investigated whether levels of TWEAK differ between male schizophrenia patients and male controls, and female schizophrenia patients and female controls. While we could not find any significant difference between female patients and female controls, TWEAK levels of male patients was significantly lower than healthy males. As we mentioned above, it may be suggested that if
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number of subjects had been higher, in addition to the statistically significant difference we found between male schizophrenia patients and male controls, these numerical differences between all other study groups could have achieved statistical significance as well.
5. Conclusion This is the first investigation about the levels of TWEAK in patients with schizophrenia. That is why we could not compare our results with other studies. Although we did not find statistically significant results in this novel study, we believe that difference could be found in future studies on TWEAK levels of patients with schizophrenia which are designed with higher number of subjects and focus on the difference between genders. In this respect, researches with non-studied TNF superfamily members like TWEAK and TRAIL could contribute to the understanding of immune-cytokine related hypotheses of schizophrenia. As mentioned above, the main limitation of this study was the comparatively small number of subjects that were recruited. The sample size is small, particularly when comparing those who are acutely ill with those who are stable. Another important limitation is the lack of taking into account of subjects' smoking and dietary habits which may affect cytokine levels. Although all patients and control subjects were in normal range of body mass index, it would be preferable if both groups were matched in regard to weight and tobacco use. Thirdly, the patients had been taking heterogeneous antipsychotics with various doses. Furthermore only one cytokine was assayed in this study sample at only one time point so its results are limited and should be reinvestigated in prospective studies.
Conflict of interest The authors declare no conflict of interest.
Acknowledgment No acknowledgment is present for the study.
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