The immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble gp130, the common signal transducer protein of various neurotrophic cytokines.

Fibromyalgia is a chronic, painful musculoskeletal disorder characterized by widespread pain, pressure hyperalgesia, morning stiffness and by an increased incidence of depressive symptoms. The etiology, however, has remained elusive. The aim of the present study was to examine the inflammatory response system (IRS) in fibromyalgia. Serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130, sIL-1R antagonist (IL-1RA) and sCD8 were determined in 33 healthy volunteers and in 21 fibromyalgia patients, classified according to the American College of Rheumatology criteria. Severity of illness was measured with several pain scales, dolorimetry and the Hamilton Depression Rating Scale (HDRS). Serum sgp130 was significantly higher and serum sCD8 significantly lower in fibromyalgia patients than in healthy volunteers. Serum sIL-6R and sIL-1RA were significantly higher in fibromyalgia patients with an increased HDRS score (> or = 16) than in normal volunteers and fibromyalgia patients with a HDRS score < 16. In fibromyalgia patients, an important part of the variance in sCD8 (50.3%) and IL-1RA (19.3%) could be explained by the HDRS score; 74.3% of the variance in sIL-6R was explained by the combined effects of pain symptoms and the HDRS score; and 25.9% of the variance in serum sgp130 was explained by stiffness. The results support the contention that pain and stiffness in fibromyalgia may be accompanied by a suppression of some aspects of the IRS and that the presence of clinically significant depressive symptoms in fibromyalgia is associated with some signs of IRS activation.     

Influence of psychological stress on immune-inflammatory variables in normal humans. Part II. Altered serum concentrations of natural anti-inflammatory agents and soluble membrane antigens of monocytes and T lymphocytes.

The effects of academic examination stress on serum concentrations of interleukin (IL)-1 receptor (R) antagonist (A), soluble(s) IL-2R, sIL-6R, soluble glycoprotein 130 (sgp130), Clara cell protein (CC16), sCD8 and sCD14 were evaluated in 38 university students. The relationships among changes in the above immune-inflammatory variables, levels of serum cortisol, and scores on the Perceived Stress Scale (PSS) or the State-Trait Anxiety Inventory (STAI) were examined. Academic examination stress was associated with significant increases in PSS and STAI scores, and in serum sgp130 and sCD8 values. Academic examination stress was associated with significantly decreased serum sCD14 concentrations in students with high, but not low, stress perception. There were stress-induced differences in serum IL-1RA, sIL-6R and CC16 concentrations between students with high vs. low stress-induced anxiety. The stress-induced increase in serum sCD8 was significantly more pronounced in male students, whereas the increase in serum sgp130 was more pronounced in female students taking contraceptive drugs. These results suggest that: (1) psychological stress induces immune-inflammatory changes pointing toward complex regulatory responses in IL-6 signalling, a decreased anti-inflammatory capacity of the serum, and interactions with T cell and monocytic activation; and that (2) sex hormones may modify stress-induced immune-inflammatory responses.     

CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis.

Interleukin-6 (IL-6) has recently been implicated in multiple sclerosis (MS), since IL-6 deficient mice were resistant to a demyelinating form of experimental autoimmune encephalomyelitis and IL-6 expression was upregulated in MS. The cytokine IL-6 and its action mediating soluble receptors (sIL-6R and sgp130) were measured in cerebrospinal fluid (CSF) and serum of 61 MS patients and 39 controls. In the presence of unchanged IL-6 concentrations, sIL-6R and sgp130 serum levels were significantly increased in MS and correlated with disease severity. Furthermore, sgp130 CSF levels were decreased in MS, suggesting a possibly altered IL-6 regulation in the CSF.     

多发性硬化患者血清与脑脊液中白介素6及其可溶性受体成分sIL-6R、sgp130的研究

目的 为探讨IL-6及其可溶性受体在多发性硬化（MS）体液免疫异常中的作用。方法 采用ELISA法测定了MS患者血清和脑脊液中IL-6及其可溶性受体成分（sIL-6R、sgp130）的水平．并与非MS的神经系统疾病、非MS神经系统炎症性疾病以及对照组进行组间比较。结果 MS患者血清及脑脊液中IL-6水平与对照组相比差异无显著性．仅见脑脊液sIL-6R升高．且其血清水平与脑脊液水平呈正相关；同时血清sgp130水平升高而脑脊液sgp130水平减低。与MS组不同．在神经系统炎症性疾病组三者血清和脑脊液水平均有升高。结论 研究结果提示sIL-6R、sgp130可能通过调控IL-6活性参与MS发病．与一般神经系统炎症性疾病相比MS的发病可能有某些不同的体液免疫机制。     

Immunological differences between patients with major depression and somatization syndrome

There is some evidence that major depression is accompanied by activation of the inflammatory response system (IRS). There is also evidence that proinflammatory cytokines and induction of IRS activation are associated with sickness behavior in experimental animals. However, no research has examined the IRS in somatization disorder. The aim of this study was to examine possible immunological differences between major depression, somatization and healthy controls. We measured the following IRS variables in patients with major depression (n=36), somatization syndrome (SSI-8; n=37), major depression and somatization (n=40) and healthy controls (n=37): interleukin-6 (IL-6); interleukin-1-receptor-antagonist (IL-1RA); plasma soluble interleukin-6 receptor (IL-6R); soluble suppressor/cytotoxic antigen (CD8); leukemia inhibitory factor (LIF-R); and Clara cell protein (CC16), an endogenous anticytokine. Serum CD8 concentrations were significantly increased in patients with major depression compared with concentrations in patients with somatization syndrome, whereas concentrations in normal controls were intermediate between those of the two groups of patients. Serum CC16 was significantly lower in major depression than in healthy controls. The highest CC16 scores were found in patients with somatization syndrome. Somatizing patients have significantly lower serum IL-6 values than normal controls and depressed patients. The present results indicate (1) an activation of the IRS in depression with signs of T-cell activation (increased CD8), monocytic activation (IL-1RA) and a lowered anti-inflammatory capacity of the serum (lower CC16) and (2) an immune alteration in somatizing syndrome, such as monocytic activation (increased IL-1RA) and indicators of lowered T-lymphocytic activity (lowered CD8 and IL-6). These results suggest different immune alterations in somatization syndrome and depression.     

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.     

Tourette综合征患者血清可溶性白细胞介素6受体与自身抗体表达水平的研究

目的 通过研究Tourette综合征(TS)患者血清自身抗体和可溶性白细胞介素6受体表达水平改变及其之间的相关性,探讨白细胞介素6受体介导的免疫调节在疾病发生中的作用.方法 应用抗脑抗体(ABAb)、抗核抗体(ANA)、可溶性白细胞介素-6受体(sIL-6R)及可溶性细胞因子受体gp130(sgp 130)的酶联免疫吸附法商品试剂盒,检测67例TS患者(TS组)和64名正常人(对照组)血清sIL-6R、sgp130及相应抗体的浓度,同时采用胶乳增强免疫比浊法检测抗链球菌溶血素O(ASO)水平.结果 TS组血清sIL-6R(44±16)pg/L,sgp130(69±25)pg/L,均显著高于对照组[(30±9)pg/L,(47±14)pg/L];差异均有统计学意义(P=0.000,P=0.000,P均＜0.01).TS组血清ABAb检出率为(67%)、ANA为(53%),均显著高于对照组(3%,25%),差异均有统计学意义(P=0.000,P＜0.01;P=0.001,P＜0.01);且ASO增高的比例(20%)高于对照组(0%)(P=0.000,P＜0.01).TS组ABAb浓度与sgp130呈负相关(r=-0.375,P＜0.05).结论 TS患者IL-6受体和自身抗体表达异常,中枢神经组织的自身免疫损伤可能参与了疾病发生发展的病理生理过程.     

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.     

IL-6 regulates MCP-1, ICAM-1 and IL-6 expression in human myoblasts

The inflammatory reaction in autoimmune polymyositis and rejection of transplanted myoblasts is characterized by mononuclear cell infiltration. In other settings monocytes are locally recruited by an IL-6-induced IL-8-to-MCP-1 switch. IL-6, upon binding to soluble gp80 (sIL-6R), can interact with membrane-bound ubiquitously expressed gp130 and activate virtually all cells (transsignaling). We found that human myoblasts could use transsignaling to produce IL-6, MCP-1 and ICAM-1; the addition of sIL-6R, binding to IL-1beta-induced IL-6, greatly increases IL-6 production. These in vitro data support the hypothesis that locally secreted IL-6 can target monocyte chemotaxis and leukocytes trafficking through an IL-6, MCP-1 and ICAM-1 modulation.     

Modulation of body temperature,interleukin-6 and leptin by oral contraceptive use

OBJECTIVES: This study examined the hypothesis that oral contraceptives (OC) influence the production of thermoregulatory cytokines, i.e. interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), soluble glycoprotein 130 (s-gp130) and leptin, and that OC-induced changes in oral temperature (T(oral)) are associated with changes in plasma concentrations of these cytokines. To determine if increases in T(oral) are part of a cytokine-driven inflammatory (acute-phase) response, circulating concentrations of the hepatic acute-phase protein C-reactive protein (CRP) were also measured. METHODS: Morning T(oral) were measured and blood samples were collected from 18 women (19- to 22-years-old) on two occasions: Once during active pill usage (quasi-luteal (QL) phase) and once when no active pills were taken (quasi-follicular (QF) phase). Plasma cytokine and CRP concentrations were measured by immunoassay. RESULTS: T(oral) and plasma leptin were higher during QL phase (36.4 +/- 0.1 degrees C, 9.3 +/- 1.0 ng/ml) than QF phase (36.1 +/- 0.1 degrees C, p < 0.01; 7.5 +/- 0.7 ng/ml, p < 0.01). Increases in T(oral) correlated with increases in plasma leptin (R = 0.55, p = 0.02) and with progestin dose (R = 0.47, p = 0.05) individually as well as with leptin and progestin combined in a multiple regression (R = 0.68, p = 0.01). Plasma IL-6 correlated with progestin dose (R = 0.62, p = 0.006). Although there were no phase-related differences in plasma IL-6, sIL-6R, s-gp130, or CRP, the variation in CRP between individuals correlated with the IL-6 agonist/antagonist ratio combined with progestin dose in a multiple regression (R = 0.71, p = 0.01). CONCLUSIONS: These results (a) implicate leptin in basal thermoregulation; (b) indicate that progestins have a significant influence on circulating IL-6 concentrations, and (c) are consistent with the concept that plasma CRP concentrations depend upon combined influences of progestins and bioavailable IL-6.     

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.     

Immune activation in multiple sclerosis: study of IL-2, sIL-2R, and gamma-IFN levels in serum and cerebrospinal fluid

Serum and cerebrospinal fluid (CSF) levels of interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), and gamma-interferon (gamma-IFN) were measured in multiple sclerosis (MS) patients, human immunodeficiency virus type 1 (HIV-1)-infected patients and normal controls (NC). Increased levels of both IL-2 and sIL-2R were found in MS serum. Moreover, 11 of 50 MS patients showed detectable levels of IL-2 in the CSF. HIV-1-infected patients had increased levels of sIL-2R in serum and, less frequently, in the CSF. gamma-IFN was never detected in serum and CSF of all the patients studied. These findings confirm preliminary reports, further stress a systemic T-cell activation in MS, and support the hypothesis that an immunologic disorder exists in such patients.     

Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration

Experimental studies suggest that cytokine production may be triggered by seizure activity. Here we determined the levels of interleukin-6 (IL-6) and its soluble receptor components (sIL-6R and sGp130) in CSF and serum from control subjects and patients after different types of seizures. IL-6 levels were increased after seizures, whereas sIL-6R levels were decreased. Interestingly, the levels of IL-6 were strongly increased after recurrent generalized tonic-clonic seizures (GTCS), whereas after single tonic-clonic or prolonged partial seizures IL-6 levels were increased to lesser extent. These results provide further support for a hypothesis of cytokine production induced by seizure activity per se.     

Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy

OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.     

雷公藤多甙对格林-巴利综合征患者IL-6及其可溶性受体的影响

目的　探讨白细胞介素 (IL 6 )及其可溶性受体 (sIL 6R)在格林 巴利综合征 (GBS)发病中的作用及免疫抑制性药物对其影响。方法　按Asbury标准选择GBS患者 4 3例 ,并进行病情严重程度分级 (0～Ⅴ级 )。其中Ⅱ级 13例 ,Ⅲ级 2 3例 ,Ⅳ级 7例。按分层随机原则 ,将GBS者分为 2组 ,分别用肾上腺皮质类固醇 (激素 )和雷公藤多甙治疗 ,在开始前、治疗后第 8周各按统一标准进行评估 1次 ,并取静脉血和脑脊液 (CSF)配对标本 2mL ,用ELISA法测定sIL 6R和双抗体夹心ELISA法测定IL 6。结果　 (1)病初GBS者血清IL 6、sIL 6R分别为 (6 9.73± 2 5.2 5)ng/L和 (4 6 .6 5± 11.59) μg/L ,明显高于对照组的 (17.94± 5.6 6 )ng/L和 (2 9.2 5± 11.0 4 )μg/L(t =13.16 ,7.33,P <0 .0 0 1) ,此外CSFIL 6、sIL 6R分别为 (14.33± 6 .6 9)ng/L和 (9.4 5± 0 .98) μg/L ,亦明显高于对照组的 (3.35± 2 .79)ng/L和 (1.38± 0 .50 ) μg/L(t=10 .0 2 ,4 8.4 8,P <0 .0 0 1)。(2 )病初GBS者CSFIL 6、sIL 6R与病情严重程度分级相关密切 (r=0 .6 7,0 .4 8,P <0 .0 1)。(3)雷公藤多甙与激素治疗后两组临床症状均有不同程度的改善。但雷公藤多甙组临床严重程度分级进步 1级以上者为 90 .3% ,明显高于激素组的6 1.9% (x2 =5.0 6 ,P     

Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning

Excessive production of pro-inflammatory cytokines in the senescent brain in response to peripheral immune stimulation is thought to induce behavioral pathology, however, few studies have examined if the increase in pro-inflammatory cytokines is accompanied by an increase in cytokine signaling. Here, we focused on IL-6 as a prototypic pro-inflammatory cytokine and used phosphorylated STAT3 as a marker of IL-6 signaling. In an initial study, IL-6 mRNA and the magnitude and duration of STAT3 activation were increased in the hippocampus of senescent mice compared to adults after i.p. injection of LPS. The LPS-induced increase in STAT3 activity was ablated in aged IL-6(-/-) mice, suggesting IL-6 is a key driver of STAT3 activity in the aged brain. To determine if IL-6 activated the classical or trans-signaling pathway, before receiving LPS i.p., aged mice were injected ICV with sgp130, an antagonist of the trans-signaling pathway. Importantly, the LPS-induced increases in both IL-6 and STAT3 activity in the hippocampus were inhibited by sgp130. To assess hippocampal function, aged mice were injected ICV with sgp130 and i.p. with LPS immediately after the acquisition phase of contextual fear conditioning, and immobility was assessed in the retention phase 48h later. LPS reduced immobility in aged mice, indicating immune activation interfered with memory consolidation. However, sgp130 blocked the deficits in contextual fear conditioning caused by LPS. Taken together, the results suggest IL-6 trans-signaling is increased in the senescent brain following peripheral LPS challenge and that sgp130 may protect against infection-related neuroinflammation and cognitive dysfunction in the aged.     

Cytokines and soluble IL-4 in patients with acute optic neuritis and multiple sclerosis

We measured the cerebrospinal fluid (CSF) and plasma concentrations of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, TNF-β, interferon (IFN)-γ, the IL-1 receptor antagonist, and soluble IL-4 receptor (sIL-4r) by ELISA in 12 patients each with acute, monosymptomatic, idiopathic optic neuritis (ON), ON as part of MS, other attack forms of MS, and in neurological control subjects. CSF concentrations of IL-1β, IL-2 and IFN-γ differed significantly between the different patient groups and were detected most commonly at the highest concentrations in patients with non-ON attacks of MS. TNF-β was detected exclusively in CSF from neurological control patients. The patients with non-ON attacks of MS also had significantly elevated concentrations of sIL-4r in plasma. Increased CSF concentrations of IL-1β, IL-2 and IFN-γ together with increased plasma concentrations of sIL-4r support the concept of MS as an autoimmune disease with preferential activation of proinflammatory or T-helper type 1-like cells. Patients with idiopathic ON or ON as part of MS may, however, differ immunologically from patients with other attack forms of MS.     

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.