Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration

Serum levels of interleukin-2 soluble receptor alpha (IL-2sR alpha), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were determined both before and during neuroleptic administration in an 8-week treatment protocol for schizophrenia. In comparison with a control group, schizophrenia patients showed significantly higher serum levels of IL-2sR alpha, IL-6 and IL-1ra at weeks 0, 1, 4 and 8, and there was a significant negative correlation between the serum level of IL-2sR alpha at week 1 and the age at illness onset. Those of the schizophrenia patients who were neuroleptic-naive had significantly higher pretreatment serum levels of IL-2sR alpha, IL-6 and IL-1ra than the controls. There were significant positive correlations between the IL-2sR alpha levels at weeks 0 and 1, and the psychopathology scores, evaluated using the positive and negative syndrome scale at week 4. IL-6 levels at weeks 0, 1 and 4 were significantly and positively correlated with the duration of illness. The IL-1ra level at week 1 was significantly and positively correlated with positive symptoms at week 1. The present study supports the suggestion that changes in the immune system are involved in the pathophysiology of schizophrenia.     

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.     

Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia

The cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6) increase during immune activation, they are released from activated astrocytes and microglial cells in the central nervous system (CNS), and they are able to enhance the catecholaminergic neurotransmission. This study focused on the soluble receptors of IL-2 and IL-6 (sIL-2R, sIL-6R) as a part of the regulation system of IL-2 and IL-6. We studied serum levels of sIL-2R in 30 schizophrenic patients not under neuroleptic medication during an acute exacerbation of the disease and reexamined these patients under neuroleptic treatment after clinical improvement. The SIL-6R levels of 39 schizophrenic patients were estimated under the same conditions. The results were compared with the levels of sIL-2R and sIL-6R in 42 healthy controls. No difference was found between the schizophrenic patients before neuroleptic treatment and the healthy controls. During neuroleptic treatment, however, there was a significant increase of sIL-2R levels and a significant decrease of the sIL-6R levels between the pre- and post-conditions. In comparison with healthy controls, the treatment group also showed increased sIL-2R levels and decreased sIL-6R levels. These results suggest that treatment with neuroleptics is associated with increased sIL-2R and decreased sIL-6R. Since sIL-2R bind and inactivate IL-2, whereas sIL-6R form an active complex with IL-6, the increase of sIL-2R and the decrease of sIL-6R together may reflect a functional down regulation of these activating cytokines. This suggests that neuroleptic therapy has a differentiated immunomodulatory effect.     

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.     

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.     

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.     

氯氮平对精神分裂症血清IL-2、IL-6的影响及临床意义

目的探讨氯氮平对精神分裂症患血清白介素-2（IL-2）、白介素-6（IL-6）水平的影响及与精神症状、体型指数变化的关系。方法选择住院的符合中国精神障碍分类与诊断标准第3版精神分裂症诊断标准的病人35例，阳性与阴性症状量表（PANSS）评分≥60分，予氯氮平治疗10周，分别于治疗前及治疗第10周末采用PANSS评估精神症状，采用酶联免疫吸附法（ELIAS）测定血清IL-2、IL-6水平。同时记录体型指数（BMI）。选取健康志愿35例作对照组，样本采集与检测同患组。结果治疗前精神分裂症患组血清IL-2水平显高于对照组（t=2．93，P=0．006），IL-6水平与对照组比较无显差异（P〉0．05）；氯氮平治疗10周末血清IL-2水平比治疗前显下降（t=3．51，P=0．001）;血清IL-6水平与治疗前相比显增高（t=2．53，P〈0．05）。治疗后精神分裂症患组体型指数显高于治疗前（t=6．02，P〈0．01）。治疗前血清IL-2水平与阳性症状评分呈显正相关（r=0．36，n=35，P=0．042）。与阴性症状、一般病理性症状、PANSS总分及体型指数均无显相关性（P〉0．05）。治疗前血清IL-6水平与各组精神症状及体型指数均无显相关性（P〉0．05）。治疗后血清IL-2下降值与阳性症状减分值呈显正相关（r=0．35，n=35，P=0．042）；IL-6增加值与各组精神症状减分值及体型指数增加值均无显相关性（P〉0．05）。结论氯氮平对精神分裂症患血清IL-2、IL-6水平有显影响，其临床意义可能与精神症状的变化有关，与氯氮平引起的体型指数变化无关。     

偏执型分裂症外周血IL-1β、TNF-α和酪氨酸羟化酶mRNA表达水平与临床症状的关系

目的检测偏执型精神分裂症患者白介素-1β、肿瘤坏死因子-α和酪氨酸羟化酶（TH）的基因表达水平,探讨其与临床症状的关系。方法采用RT-PCR和半定量技术,分别检测39例偏执型精神分裂症患者和30例正常对照外周血单个核细胞IL-1β、TNF-α和TH的基因表达水平,同时应用PANSS量表评定偏执型精神分裂症患者临床症状。结果研究显示病例组的IL-1β、TNF-α、TH基因表达水平均显著高于正常对照组（P〈0.01）。且同时发现IL-1β（r=0.420）、TNF-α（r=0.430）基因表达水平与PANSS量表的一般病理症状分显著相关（P〈0.01）。结论偏执型精神分裂症患者可能存在致炎性细胞因子和儿茶酚胺类神经递质的过度表达;致炎性细胞因子可能参与偏执型精神分裂症一般病理症状的形成。     

奎的平与氯氮平治疗对精神分裂症的疗效及其血清细胞因子水平变化关系的对照分析

目的 比较奎的平与氯氮平对精神分裂症的疗效与血清白介素-2(IL-2)、可溶性白介素-2受体(SIL-2R)水平变化的关系。方法 对60例精神分裂症患者随机分为奎的平组、氯氮平组进行6周治疗，采用PANSS量表评定疗效，同时测定血清IL-2、SIL-2水平。结果 两药疗效相当，并与显著下降的IL-2水平相关，两药对SIL-2R的影响差异显著。结论 奎的平与氯氮平对精神分裂症的疗效可能与降低血清IL-2水平有关，而与血清SIL-2R水平无关。     

白介素—8和γ—干扰素在精神分裂症患者中表达水平的研究

目的 探讨白细胞介素—8和γ—干扰素表达水平与精神分裂症的关系.方法 对96例符合CCMD-3精神分裂症诊断标准的患者,用利培酮治疗.在治疗前后检测血清IL-8、INF-γ水平,在治疗前后评定PANSS和TESS量表,并采用酶联免疫试验(ELISA)检测血清IL-8和INF-γ含量.结果 首发精神分裂症血清IL-8明显高于正常组(P＜0.05),男女之间无差异;血清IL-8与病程、PANSS总分均呈正相关(r=0.627,0.592,P＜0.05),患者治疗前后血清INF-γ明显低于正常组,治疗前后变化无显著性差异(P＞0.05).结论 精神分裂症发生中IL-8产生增加并反映早期病情严重程度,患者INF-γ产生不足.     

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.     

精神分裂症下丘脑-垂体-肾上腺轴功能研究

目的：了解精神分裂症患者治疗前后下丘脑-垂体-肾上腺（HPA）轴促肾上腺皮质激素释放激素（CRH）、促肾上腺皮质激素（ACTH）和皮质醇（CORT）的分泌水平和节律变化。方法：在治疗前、治疗2周、4周、8周用放射免疫测定法检测30例精神分裂症患者全天3次（8：00,16：00,24：00）HPA轴激素的水平,并采用阳性与阴性症状量表（PANSS）评定精神症状。比较治疗前后患者HPA激素水平和分泌节律,以及全天3次CORT总量与PANSS分的关系。10名正常对照组HPA水平采用同样方法检测。结果：患者治疗前HPA轴激素水平均明显高于同时点对照组（P均〈0.01）;治疗8周,HPA轴激素水平有明显降低,但仍高于对照组（P〈0.05）。治疗前,患者激素分泌节律紊乱;治疗8周后节律正常。全天3次CORT总量与PANSS总分、阳性症状分、一般精神病理分呈显著正相关（r=0.351、r=0.425、r=0.406,P〈0.05）,与阴性症状分无显著相关（r=0.297,P〉0.05）。结论：精神分裂症患者存在HPA轴激素分泌和节律的异常,精神症状越严重,全天皮质醇总量越高。     

慢性精神分裂症住院患者的程式化技能训练

目的:探讨程式化技能训练对慢性精神分裂症住院患者的康复效果.方法:将 120 例住院患者随机分成训练组和对照组各 60 例,对训练组进行 8 周的程式化训练,然后全部随访 24 周.采用阳性与阴性症状量表(PANSS),自知力与治疗态度问卷(ITAQ)和 Morningside 康复状态量表(MRSS)进行评估.结果:训练组的 PANSS 总分、阴性症状分和一般精神病理分及 ITAQ 分以及 MPSS 各量表分在训练第 20 周末起,都明显优于对照组.结论:程式化技能训练可使慢性精神分裂症住院患者增进多方面的康复效果.     

利培酮、奎的平对精神分裂症疗效及与血清细胞因子水平变化的关系

目的 比较利培酮和奎的平对精神分裂症的临床疗效与血清白介素-2(IL-2)、可溶性白介素-2受体(SIL-2R)水平变化的关系。方法将60例精神分裂症患者随机分为利培酮组和奎的平组进行6周治疗，采用PANSS量表评定疗效，同时测定血清IL-2、SIL-2水平。结果 两药疗效相当，其阳性症状的改善与显著下降的IL-2水平相关。结论 利培酮和奎的平对精神分裂症的阳性症状的疗效可能与降低血清IL-2水平有关。     

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.     

Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer's disease patients

Evidence from epidemiological, clinical and experimental studies favour the hypothesis that inflammatory events are part of the neuropathology in Alzheimer's disease. Proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been found in activated microglia in the vicinity of amyloid plaques in Alzheimer's disease brain. In the present study, the levels of soluble IL-1 receptor type II (sIL-1R type II), IL-1 receptor antagonist (IL-1ra), IL-1beta, IL-6 and TNF-alpha were analyzed in cerebrospinal fluid (CSF) samples from Alzheimer's disease patients and control subjects. The levels of sIL-1R type II were significantly higher in CSF from Alzheimer's disease patients than in CSF samples from control subjects (38.5+/-8 pg/ml (mean+/-S.E.M.) vs. 7.9+/-4 pg/ml, p<0.05). Measurements of the proinflammatory cytokines IL-6 and TNF-alpha showed no significant difference between the two groups, and the levels of IL-1beta and IL-1ra in the present material were too low to permit detection. The increased levels of sIL-1R type II may reflect a compensatory mechanism to balance an increased release of IL-1 receptor agonists in the Alzheimer's disease brain.     

A longitudinal study on IL-2, sIL-2R, IL-4 and IFN-gamma in multiple sclerosis CSF and serum.

The cerebrospinal fluid (CSF) and serum levels of interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) were longitudinally investigated in 20 multiple sclerosis (MS) patients. There were 80 paired CSF and serum samples (range 2-8 per patient) covering a 1-5 year (mean 2.5 year) period. Increased levels of IL-2 and sIL-2R were found in 56 and 71%, respectively, of MS sera. In all patients, one or several sera (totally 89%) exhibited values above the normal range for either one of the components or both. The occurrence of IL-2 or sIL-2R positive CSF specimens was much lower, 15 and 9%, respectively. Only 3 MS sera (from one patient) had clearly detectable IL-4 and no CSF samples were definitely positive. IFN-gamma was undetectable in all serum and CSF specimens. No correlations were found between the immunological parameters and the clinical disease activity. The cytokine patterns in MS give strong support for the presence of a systemic T-cell activation. Furthermore, the data argue for a predominant activation of an IL-2- and sIL-2R-producing but not IL-4-producing T-helper (Th) lymphocyte subpopulation, Th1/CD4 + CD45R + cells.     

Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder

Alterations in the immune system may have importance for the pathophysiology of depression. Several studies have linked increased production of pro-inflammatory cytokines to depression and depressive symptoms. There is growing evidence that antidepressive treatment may influence the production of pro-and anti-inflammatory cytokines. In the present study we aimed to find associations between the levels of soluble interleukin-2 receptor (sIL-2R), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) and the response to antidepressant treatment in patients with major depression. Our study group consisted of 100 patients (35 males and 65 females) who were treated with escitalopram 10-20 mg/day for 12 weeks. Responders and non-responders were identified according to Montgomery-Asberg's Depression Rating Scale (MADRS) scores. The levels of cytokines were measured at baseline and at 4th and 12th week of the treatment and compared to cytokine concentrations in healthy volunteers (n=45; 19 males and 26 females). Our data indicated that a higher level of TNF-alpha might predict a non-response to treatment with escitalopram and that changes in concentrations of sIL-2R during the treatment were different in responders and non-responders.     

利培酮和氯氮平对首发精神分裂症患者血浆细胞因子的影响

目的 比较利培酮和氯氮平对首发精神分裂症患者血浆细胞因子影响的差异。方法 用酶联免疫吸附法(ELISA)测定利培酮和氯氮平两组各30例患者治疗6周前后的血浆白细胞介素-2(IL-2)、可溶性白细胞介素-2受体(sIL-2 R)、白细胞介素-6(IL-6)及可溶性白细胞介素-6受体(sIL-6R)的浓度,两组间进行比较,每组治疗前后各自进行比较。结果 两组间比较,血浆细胞因子水平无显著性差异(P>0.05);治疗前后各自进行比较,每组血浆IL-2及sIL-6R水平显著下降(P<0.05),IL-6水平显著升高(P<0.05),sIL-2R治疗前后无显著性差异(P>0.05)。结论 利培酮和氯氮平治疗均对首发精神分裂症患者的IL-2、IL-6及sIL-6R水平产生显著性影响,对sIL-2R水平影响不显著;利培酮和氯氮平对首发精神分裂症患者细胞因子水平的影响基本一致。     

Impact of gender and menstrual cycle phase on plasma cytokine concentrations

OBJECTIVE: The lifetime prevalence of major depression is twice as high in females as in males. Depression is known to increase at periods where there are changes in gonadal hormones. We examined pro- and anti-inflammatory cytokine levels during the normal menstrual cycle of healthy females compared to similar time points in healthy males. METHODS: Plasma concentrations of interleukin (IL)-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha) and soluble IL-6 receptor (sIL-6R) were measured with enzyme-linked immunosorbent assays in healthy females during the normal ovulatory menstrual cycle and also in males at similar time points. RESULTS: The luteal phase of the menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-alpha compared to the early follicular phase. No change was observed in IL-6, IL-8 and IL-10 concentration throughout the menstrual cycle. We found IL-4 positively correlated with oestrogen while TNF-alpha positively correlated with progesterone. Females were found to have significantly higher concentrations of TNF-alpha and sIL-6R across all phases of the menstrual cycle, compared to males across similar time points. CONCLUSION: The normal menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-alpha in the luteal phase compared to the early follicular phase. Females have significantly higher concentrations of sIL-6R and TNF-alpha at all time points across the menstrual cycle than males.