Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients

Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL-6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis × genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia.     

In-vitro Immunomodulatory Effects of Haloperidol and Perazine in Schizophrenia

Summary: There are some reports describing concurrent changes in lymphocytic and monocytic activities in schizophrenia. In this study we investigated T cell activity in schizophrenic patients by measuring the release of interleukin-2 (IL-2) and soluble interleukin-2 receptor (sIL-2R) by T cells and the percentages of CD4+ and CD8+ cells in blood. The release of IL-2 and sIL-2R by T cells was evaluated in dilute whole blood after in-vitro stimulation with phytohemagglutinin. IL-2 levels and the percentage of CD4-cells tended to decrease and sIL-2R levels decreased significantly in schizophrenic patients. Haloperidol and perazine significantly decreased IL-2 levels and increased sIL-2R levels and the percentage CD4-cells. IL-2 and sIL-2R levels were lower in patients with a predominance of positive symptoms. The neuroleptic-induced increase in sIL-2R levels was higher in patients with a predominance of positive symptoms compared with those in whom both positive and negative symptoms were severe. The study has shown that T-cell activity is reduced in schizophrenia and that neuroleptics may have immunomodulatory properties.     

Effect of neuroleptic administration on serum levels of soluble IL-2 receptor-alpha and IL-1 receptor antagonist in schizophrenic patients

Activation of the inflammatory response system has been reported in schizophrenia. Levels of serum IL-1 receptor antagonist (IL-1ra) and soluble IL-2 receptor (sIL-2R(alpha)) were studied in 32 schizophrenic and 22 age- and sex-matched healthy subjects before and after an 8-week treatment protocol. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). At weeks 0 and 8, sIL-2R(alpha) levels were significantly higher than in the schizophrenic patients, as well as in a neuroleptic-naive subgroup, than in controls. Patients' sIL-2R(alpha) levels did not vary significantly between weeks 0 and 8. IL-1ra levels in controls did not differ significantly from those in patients at week 0 but were significantly lower at week 8. The patients' serum IL-1ra levels varied significantly between weeks 0 and 8. IL-1ra levels were significantly higher in the subgroup of neuroleptic-naive patients at week 0 than in controls. Levels of sIL-2R(alpha) at week 0 were positively correlated with PANSS positive and negative symptom scores at week 8, and levels at week 8 were positively correlated with PANSS total, positive symptom, and negative symptom scores at week 8. IL-1ra levels at week 0 were positively correlated with PANSS scores at week 8. There were positive correlations between both delta (baseline values minus endline values) IL-1ra and delta sIL-2R(alpha) levels and delta PANSS negative symptoms. The results provide evidence for immune activation in some schizophrenic patients and suggest that medication differentially affects the production of sIL-2R(alpha) and IL-1ra.     

Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine

The purpose of this study was to investigate immune-inflammatory markers in schizophrenia and the effects of chronic treatment with clozapine, an atypical antipsychotic agent, on these variables. Toward this end, we measured interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and sIL-2R in the blood of 26 normal controls and 14 schizophrenic patients before and after treatment with clozapine. The sIL-2R and IL-6 levels were significantly higher in younger (<35 years) schizophrenic subjects than in normal controls and older (≥ 35 years) schizophrenic subjects. The sIL-6R levels were significantly lower in schizophrenic subjects than in normal controls. Chronic treatment with clozapine significantly increased the blood concentration of sIL-2R; the increases in the latter were significantly related to the dose of clozapine but not to changes in severity of positive or negative symptoms. We conclude that: (a) schizophrenia in younger people is accompanied by increased IL-6 and sIL-2R secretion; and (b) subchronic treatment with clozapine increases sIL-2R levels. Increased plasma sIL-2R may be one mechanism by which neuroleptics exhibit their immunosuppressive effects.     

Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer''s disease

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimer's disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.     

Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis.

It has been hypothesized that the immune system plays a pathogenetic role in psychiatric disorders, in particular in major depression and schizophrenia. This hypothesis is supported by a number of reports on altered circulating levels and in vitro production of cytokines in these disorders. However, the respective evidence is not consistent. This may be in part due to an incomplete control for numerous confounding influences in earlier studies. We investigated the plasma levels of cytokines and soluble cytokine receptors in psychiatric patients (N = 361) upon hospital admission and compared the results to those obtained in healthy controls (N = 64). By multiple regression analysis we found that circulating levels of interleukin-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R p55, sTNF-R p75) and IL-6 were significantly affected by age, the body mass index (BMI), gender, smoking habits, ongoing or recent infectious diseases, or prior medication. Cytokine or cytokine receptor levels were significantly increased in patients treated with clozapine (sIL-2R, sTNF-R p75), lithium (TNF-alpha, sTNF-R p75, IL-6) or benzodiazepines (TNF-alpha, sTNF-R p75). Taking all these confounding factors into account, we found no evidence for disease-related alterations in the levels of IL-1Ra, sIL-2R, sTNF-R p75 and IL-6, whereas levels of TNF-alpha and sTNF-R p55 in major depression and sTNF-R p55 in schizophrenia were slightly decreased compared to healthy controls. We conclude that, if confounding factors are carefully taken into account, plasma levels of the above mentioned cytokines and cytokine receptors yield little, if any, evidence for immunopathology in schizophrenia or major depression.     

In-vitro immunomodulatory effects of haloperidol and perazine in schizophrenia.

There are some reports describing concurrent changes in lymphocytic and monocytic activities in schizophrenia. In this study we investigated T cell activity in schizophrenic patients by measuring the release of interleukin-2 (IL-2) and soluble interleukin-2 receptor (sIL-2R) by T cells and the percentages of CD4+ and CD8+ cells in blood. The release of IL-2 and sIL-2R by T cells was evaluated in dilute whole blood after in-vitro stimulation with phytohemagglutinin. IL-2 levels and the percentage of CD4-cells tended to decrease and sIL-2R levels decreased significantly in schizophrenic patients. Haloperidol and perazine significantly decreased IL-2 levels and increased sIL-2R levels and the percentage CD4-cells. IL-2 and sIL-2R levels were lower in patients with a predominance of positive symptoms. The neuroleptic-induced increase in sIL-2R levels was higher in patients with a predominance of positive symptoms compared with those in whom both positive and negative symptoms were severe. The study has shown that T-cell activity is reduced in schizophrenia and that neuroleptics may have immunomodulatory properties.     

Serum and CSF levels of IL-2, sIL-2R, TNF-alpha, and IL-1 beta in chronic progressive multiple sclerosis: expected lack of clinical utility

We measured interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) by ELISA in paired sera and CSF from 50 chronic progressive multiple sclerosis (CPMS) patients during worsening disability, 19 patients with other neurologic diseases (OND), and in sera from 40 healthy volunteers. In the CPMS patients, 28% (14/50), 10% (5/50), 16% (8/50), and 6% (3/50) had elevated serum levels of IL-2, sIL-2R, TNF-alpha and IL-1 beta, respectively, compared with healthy controls. The only analyte we detected in the CSF was IL-2 in 1 CPMS patient (1/50, 2%). We also saw elevated serum sIL-2R in 16% (3/19) of OND patients. We found no significant difference in mean levels of serum sIL-2R between the 3 groups. Our study, the largest to date of CPMS patients, shows that serum and CSF levels of IL-2, sIL-2R, TNF-alpha, or IL-1 beta are not sensitive for, and the serum sIL-2R level is not specific for, CPMS. Therefore, measurement of these analytes will not be clinically useful for therapeutic or prognostic purposes in the majority of CPMS patients.     

Diurnal and sleep-wake dependent variations of soluble TNF- and IL-2 receptors in healthy volunteers

There is very little published information on the diurnal variation of cytokines and their receptors, in healthy individuals during normal sleep-wake patterns or during sustained wakefulness. The aim of the current investigation was to characterize concentrations of soluble tumor necrosis factor receptors (sTNF-Rs) and interleukin-2 receptor (sIL-2R) during normal sleep and wakefulness, as well as during a 24 h vigil. Plasma levels of the sTNF-R p55, sTNF-R p75, and sIL-2R did not differ significantly between nocturnal sleep and nocturnal wakefulness. Rhythmic analysis (2-h intervals) revealed significant diurnal variations for both sTNF-R p55 and sTNF-R p75, but not levels of sIL-2R. Diurnal variations of both sTNF-Rs were characterized by a single cosine curve with an average peak near 06:00 h in the morning. This peak occurred well before that of cortisol, and fluctuated inversely with the diurnal rhythm of temperature. These diurnal variations in sTNF-Rs levels are consistent with the hypothesis that the TNF system plays a role in normal diurnal temperature regulation.     

Autoantibodies against 60-kDa heat shock protein in schizophrenia

Immunological abnormalities in schizophrenic patients have been reported for many years. However, the question of whether these parameters are involved in the pathophysiology of the disorder or represent treatment effects is still not answered. We investigated a combination of humoral and soluble immune parameters in 30 unmedicated schizophrenic patients before and during antipsychotic treatment and in 31 healthy controls. The aim of our study was to unravel an underlying immune process, to elucidate the influence of neuroleptic treatment and to identify a subgroup of schizophrenics. Antibodies against human 60-kDa heat-shock protein (HSP60), serum levels of soluble ICAM-1 and IL-2R were determined and correlated with parameters of blood–brain barrier and of psychopathology. In 10% of the drug-free but in 20% of the medicated schizophrenics, especially in females, we observed immunoreactivity against HSP60, high levels of IgG in CSF and a blood–brain barrier impairment. The high HSP antibody titres correlated with high levels of sIL-2R and sICAM-1. Only one of the controls showed antibodies against HSP60. Our results suggest that the observed immunological alterations are more pronounced during neuroleptic treatment than in the drug-free state. Whether or not this differential response to treatment with altered antibody production represents a subgroup of patients has yet to be determined. Received: 13 November 1997 / Accepted: 15 September 1998     

糖皮质激素对重症肌无力患者周围血IL－2活性及sIL－2R水平的影响

检测了４２例重症肌无力（ＭＧ）患者周围血单个核细胞（ＰＢＭＣ）白细胞介素－２（ＩＬ－２）活性及血清可溶性白细胞介素－２受体（ｓＩＬ－２Ｒ）水平，重点观察了１４例ＭＧ患者在糖皮质激素（ＧＣ）治疗后ＩＬ－２活性及ｓＩＬ－２Ｒ水平变化。结果显示，ＭＧ患者ＰＢＭＣＩＬ－２活性显著低于正常对照组，而血清ｓＩＬ－２Ｒ水平显著高于正常对照组，且ＭＧ患者ＩＬ－２活性与ｓＩＬ－２Ｒ水平之间呈显著负相关；应用ＧＣ治疗后，ＩＬ－２活性显著升高，ｓＩＬ－２Ｒ水平显著下降。提示ＭＧ患者ＩＬ－２活性变化与ｓＩＬ－２Ｒ水平密切相关，ＧＣ可通过影响ＩＬ－２活性及ｓＩＬ－２Ｒ水平而发挥免疫治疗作用。     

High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder.

BACKGROUND: Previously, we found an increased prevalence of thyroid autoantibodies in patients with bipolar disorder. In the present study, we investigated other signs of immune activation in bipolar patients, in particular an activation of the T cell system. METHODS: Fluorescence activated cell scanning (FACS) analysis was performed on lymphocytes of 64 outpatients with DSM-IV bipolar disorder using the T cell marker CD3 in combination with the activation markers MHC-class II, CD25, CD69 or CD71. In 34 patients, these assays were repeated after an interval of 2 years. In addition, T cell activation was determined by measuring serum soluble IL-2 receptor (sIL-2R) in 172 bipolar outpatients. Outcomes were compared with a healthy control group. RESULTS: Significantly higher numbers of circulating activated T cells and raised sIL-2R levels were found in euthymic, manic, and depressed bipolar patients when compared with healthy controls. In general, these abnormalities were stable over time. Manic patients showed significantly higher levels of sIL-2R in comparison with depressed patients. CONCLUSION: The T cell system was found to be activated in both symptomatic and euthymic patients with bipolar disorder. The pathophysiological significance of these findings remains to be explored.     

Serum interleukin-6 soluble receptor in relation to interleukin-6 in stroke patients

Cerebral ischemia triggers interleukin-6 (IL-6) release into blood. IL-6 is a key mediator of acute phase reaction. Markers of acute phase reaction (C-reactive protein, fibrinogen, fever) have been linked to poor prognosis in stroke patients. Interleukin-6 soluble receptor (sIL-6R) can potentiate IL-6 pro-inflammatory activity. The aim of this study was to investigate the relationship between IL-6 and sIL-6R in stroke patients. Serum cytokine levels were measured in 18 stroke patients and 13 controls using the ELISA method. On the second day of stroke, IL-6 levels were significantly higher in stroke patients than in controls; sIL-6R levels did not differ significantly between groups. Three months after stroke, IL-6 levels did not differ significantly between groups; sIL-6R levels were significantly decreased in stroke patients when compared with that in controls and with levels in acute phase of stroke. Decreased sIL-6R early after stroke might reflect a regulatory mechanism attenuating inflammatory response.     

重症肌无力患者细胞免疫水平的检测及临床意义

目的 :探讨周围血中 T细胞亚群、NK细胞、细胞膜白细胞介素 - 2受体、可溶性白细胞介素 - 2受体的阳性细胞与 MG发病及临床疗效的关系。方法 :1.应用流式细胞仪检测外周围血 m IL- 2 R(CD2 5)阳性细胞、NK(CD5 6 )和T细胞亚群 (CD3 、CD4、CD8)的相对计数。 2 .用富氏双抗体夹心 EL ISA方法检测血清 s IL- 2 R。结果 :1.MG患者血清s IL- 2 R水平明显高于健康对照组 ,激素治疗后较治疗前明显下降 ;2 .NK和 CD4阳性细胞在治疗前均明显高于正常 ,治疗后明显下降 ;3.CD3 阳性细胞在激素治疗前后无明显改变 ;4.m IL- 2 R(CD2 5)阳性细胞数无明显改变。结论 :1.血清中的 s IL- 2 R,NK细胞的测定可对该病进行动态观察 ;2 .CD4增高 ,CD8下降提示免疫功能紊乱 ;3.m IL- 2 R阳性细胞百分率不能直接反映 MG的免疫功能紊乱。     

Increased tumor necrosis factor-alpha concentrations with interleukin-4 concentrations in exacerbations of schizophrenia

Several studies have indicated that cytokines may be involved in the pathophysiology of schizophrenia. Previous studies, however, have yielded contradictory results; in this study we assess the plasma levels of both T-helper-1 (Th1) and T-helper-2 (Th2) cytokines in patients with acute exacerbations of schizophrenia. Plasma concentrations of interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and soluble receptor of interleukin-6 (sIL-6R) were measured with high sensitivity, enzyme-linked immunosorbent assays (ELISA) in patients with acute exacerbations of schizophrenia as compared with healthy controls. Patients with an acute exacerbation of schizophrenia had significantly increased production of TNF-alpha and significantly reduced production of IL-4 as compared with healthy subjects. No significant difference was observed in IL-6, sIL-6R, IL-8 and IL-10. Acute exacerbations of schizophrenia are associated with increased TNF-alpha concentrations (Th1) with concomitantly reduced concentrations of IL-4 (Th2) and a resulting increased TNF-alpha/IL-4 ratio.     

Plasma soluble interleukin-2-receptor in depression: relationships to plasma neopterin and serum IL-2 concentrations and HPA-axis activity

The present study examined the plasma concentration of the soluble interleukin-2-receptor (sIL-2R) in depressed subjects in relation to hypothalamic pituitary adrenal (HPA) axis function and plasma neopterin and serum IL-2 concentrations. Plasma sIL-2R concentration was significantly higher in depressed patients (n = 47) than in controls (n = 19). There were no significant correlations between plasma sIL-2R and severity of illness. In the depressed subjects, there was a highly significant relationship between plasma sIL-2R and neopterin concentrations. Depressed patients with pathologically increased plasma neopterin levels had significantly higher plasma sIL-2R values than those with normal serum neopterin. There were no significant relationships between plasma sIL-2R and indices of HPA-axis function in depression. There was no significant effect of dexamethasone administration on sIL-2R levels. Significantly more depressed subjects had measurable serum IL-2 levels than normal controls. Our data support the notion that a moderate activation of cell-mediated immunity may play a role in the pathophysiology of depression.     

Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders

Background

Some but not all antipsychotics have been shown to modulate plasma cytokine levels in schizophrenia patients. Thus far, the most consistent finding has been the increase in plasma levels of soluble interleukin (IL)-2 receptor (sIL-2R) associated with clozapine treatment. Quetiapine is a second-generation antipsychotic with a pharmacological profile similar to that of clozapine, but its immunomodulatory effects have not been investigated in schizophrenia yet. The purpose of this exploratory study was to examine the changes in plasma levels of sIL-2R in schizophrenia during quetiapine treatment and association with psychopathology.

Methods

Participants were 29 schizophrenia-spectrum disorder patients (DSM-IV criteria), and 28 healthy controls. Patients had a comorbid substance use disorder (cannabis > alcohol > cocaine), since quetiapine is increasingly used in this population of dual diagnosis. No participant suffered from infection or overt inflammatory diseases. On baseline, patients taking mostly second-generation antipsychotics were switched to quetiapine for a 12-week open-label trial. Five patients were drop-outs. Mean dose of quetiapine for trial completers (n = 24) was 466.6 mg ± 227.3. Psychiatric variables were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Plasma sIL-2R levels were assessed at baseline, weeks 6 and 12 in patients, and in healthy controls, using sandwich immunoassay. Plasma IL-6 and IL-1 receptor antagonist (IL-1RA) were measured for comparison purposes.

Results

On baseline, plasma sIL-2R, IL-6 and IL-1RA levels were higher in dual-diagnosis patients, compared to controls. Plasma sIL-2R further increased after quetiapine treatment (p = 0.037), while plasma IL-6 and IL-1RA did not change. Clinical improvements were observed in positive, negative and depressive symptoms, and substance abuse severity (all p < 0.01). Interestingly, changes in sIL-2R levels during treatment were inversely correlated with changes in positive symptoms (r = − 0.524; p = 0.009). That is, increases in sIL-2R levels were associated with reductions in positive symptoms.

Conclusion

These data show that quetiapine elevates, like clozapine, sIL-2R levels in schizophrenia. Furthermore, the results suggest that sIL-2R alterations in schizophrenia rely on complex interplays between antipsychotics and the positive symptoms of the disorder. Future randomized controlled trials involving larger samples of schizophrenia patients are warranted to determine whether changes in plasma sIL-2R are quetiapine-related.     

Notable increased cerebrospinal fluid levels of soluble interleukin-6 receptors in neuromyelitis optica

Background: IL-6 is a proin?ammatory cytokine which is involved in the maintenance of the humoral response in various autoimmune disorders. Cerebrospinal fluid (CSF) IL-6 has shown to be increased in neuromyelitis optica (NMO). The soluble form of IL-6 receptor (sIL-6R), which links to IL-6, can activate biological responses in cells. Whether or not sIL-6R is altered in NMO has not been clarified. Objective: To measure CSF IL-6 and sIL-6R in NMO and multiple sclerosis (MS) patients, and investigate whether IL-6 and sIL-6R have possible uses as sensitive biomarkers for diseases activity. Methods: CSF concentrations of IL-6 and sIL-6R were measured by an ELISA in NMO (n = 22) and MS (n = 18) patients, as well as control subjects (n = 14). Results: The concentration of IL-6 levels were higher in NMO compared to MS (p = 0.032) and the controls (p = 0.023). The levels of sIL-6R were also higher in NMO compared to MS (p = 0.002) and the controls (p < 0.001). CSF sIL-6R was associated with an Expanded Disability Status Scale score in NMO (p = 0.005) but not in MS (p = 0.891). In the MS subgroup, sIL-6R concentrations were associated with CSF white blood cells (p = 0.034). Conclusions: Our study revealed that CSF sIL-6R was increased in NMO patients, and correlated with clinical presentations.     

Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events.

BACKGROUND: Recently, it has been reported that serum interleukin-1 beta (IL-1 beta), but not soluble IL-2 receptor (sIL-2R), concentrations were significantly higher in patients with posttraumatic stress disorder (PTSD) than in normal volunteers, and that psychological stress in humans is associated with increased secretion of proinflammatory cytokines, such as IL-6. METHODS: The aim of the present study was to examine the inflammatory response system in patients with PTSD through measurements of serum IL-6, sIL-6R, sgp130 (the IL-6 signal transducing protein), sIL-1R antagonist (sIL-1RA; an endogenous IL-1 receptor antagonist), CC16 (an endogenous anticytokine), and sCD8 (the T suppressor-cytotoxic antigen). RESULTS: Serum IL-6 and sIL-6R, but not sgp130, sIL-RA, CC16, or sCD8, concentrations were significantly higher in PTSD patients than in normal volunteers. Serum sIL-6R concentrations were significantly higher in PTSD patients with concurrent major depression than in PTSD patients without major depression and normal volunteers. There were no significant relationships between serum IL-6 or sIL-6R and severity measures of PTSD. CONCLUSIONS: The results suggest that PTSD is associated with increased IL-6 signaling. It is hypothesized that stress-induced secretion of proinflammatory cytokines is involved in the catecholaminergic modulation of anxiety reactions.