Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Associations between serum estradiol and IL-6/sIL-6R/sgp130 complex in female patients with major depressive disorder.

BACKGROUND: It has been hypothesized that the IL-6/sIL-6R/sgp130 complex, an inflammatory complex, plays a critical role in the pathogenesis of major depressive disorder (MDD). Estradiol (E2) is a sex steroid hormone involved in emotional regulation and MDD. This study aimed to investigate the relationship between E2 and IL-6/sIL-6R/sgp130 complex in patients with MDD. METHODS: Using enzyme-linked immunosorbent assay, the levels of IL-6, sIL-6Rα, and sgp130 were compared between 117 female patients with MDD and 122 healthy controls.The serum concentrations of E2 and other biomarkers were also measured. RESULTS: (1) The serum levels of IL-6 and sIL-6Rα in patients with MDD were significantly higher than those in the control group, while the serum levels of sgp130 and E2 were significantly lower (all P < 0.05). (2) Low levels of E2 were associated with high levels of IL-6 and low levels of sgp130 (all P < 0.01). (3) HAMD-24 score was positively correlated with the serum level of IL-6, but negatively correlated with the serum levels of sgp130 and E2(all P < 0.05). (4) IL-6 and sgp130 had certain prognostic values in MDD, and the combination of various indicators showed a significantly superior prognostic value. CONCLUSIONS: The IL6/sIL-6R/sgp130 complex in female patients with MDD was closely related to E2 level. In addition, IL-6 and sgp130 may be valuable serum biomarkers for the diagnosis and prognosis of MDD in women.

Dynamics of the Levels of Interleukin 6, Its Soluble Receptor, and Soluble Glycoprotein 130 in Patients with Chronic Heart Failure and Preserved or Reduced Ejection Fraction.

The features of IL-6 trans-signaling were studied in patients with heart failure with reduced (n=74) and preserved (n=31) ejection fraction (EF) during acute decompensation of HF (ADHF) and after 1 year. Patients with ADHF with reduced EF demonstrated higher levels of IL-6 and soluble glycoprotein 130 in comparison with those in patients with preserved EF: 10.18 (7.07; 16.14) pg/ml vs 6.35 (3.52; 11.00) pg/ml and 543.46 (455.37; 634.43) ng/ml vs 498.50 (408.16; 632.23) ng/ml, respectively. The levels of soluble IL-6 receptor little differed in these groups: 57.82 (47.55; 79.85) ng/ml vs 61.30 (44.97; 78.08) ng/ml. After 1 year, the levels of IL-6 in HF patients with reduced EF significantly decreased (5.36 (3.35; 8.35) pg/ml), while in patients with preserved EF, the decrease in this parameter was less pronounced (5.86 (4.05; 7.32) pg/ml), and the difference between groups disappeared. The levels of soluble glycoprotein 130 increased in both groups: 448.06 (357.74; 550.67) ng/ml vs 385.35 (344.29; 523.72) ng/ml. It should be noted that after 1 year (in stable patients), the levels of soluble IL-6 receptor increased in both groups: 65.75 (54.84; 75.39) ng/ml vs 70.81 (57.51; 82.25) ng/ml. Thus, despite the high levels of IL-6 in HF patients with reduced EF, the potential limiting IL-6 trans-signaling in these patients is higher than in patients with preserved EF.

Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors.

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed. Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05-1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (-634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively). Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.

Effects of soluble glycoprotein 130 on expression of p-STAT3 and vascular endothelial growth factor-A in retina of mice with diabetes mellitus / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To observe the effect of soluble glycoprotein 130(sgp130)on expression of p-STAT3 and vascular endothelial growth factor(VEGF)-A in retina of mice with diabetes mellitus(DM), and explore the possibility of sgp130 in interfering with inflammatory damage of diabetic retinopathy(DR).METHODS: A total of 45 mice were randomly divided into normal group, DM group and sgp130 group. DM models were made in DM group and sgp130 group with streptozotocin. No special intervention was given to normal group and DM group, but sgp130 group was given intravitreal injection of 1.5mg/mL sgp130 2μL at the 1 and 5wk. After 10wk, all the mice were sacrificed to assess the protein expression of interleukin 6(IL-6), p-STAT3 and VEGF-A in the retina.RESULTS: The expressions of IL-6, p-STAT3 and VEGF-A in retina of DM group were higher than those of normal group at 10wk(all P<0.01). The expression of p-STAT3 and VEGF-A in sgp130 group were lower than those in DM group(all P<0.01).CONCLUSION: The sgp130 can selectively antagonize the trans signal transduction pathway of IL-6, down-regulate the expression of downstream inflammatory factors VEGF-A, and it may be used in the intervention of retinal inflammatory damage related with IL-6 in DM.

The change of interleukin -6, soluble interleukin - 6 receptor and soluble glycoprotein 130 levels in patients with lung injury caused by paraquat poisoning and its clinical significance / 中国医师进修杂志

Objective:To investigate the change of interleukin-6(IL-6), soluble interleukin-6 receptor(sIL-6R) and soluble glycoprotein 130(sgp130) levels in patients with lung injury caused by paraquat poisoning and its clinical significance.Methods:Fifty patients with paraquat poisoning and lung injury admitted to Ba′nan District People′s Hospital of Chongqing from December 2017 to December 2019 were selected as the observation group, and 30 healthy patients were selected as the control group. The serum levels of IL-6, sIL-6R and sgp130 in two groups was detected with double-antibody sandwich enzyme-linked immunosorbent assay and compared. Pearson correlation analysis was performed on the relationship between serum IL-6, sIL-6R and sgp130 and the acute physiological and chronic health status assessment(APACHE)- Ⅱ score of patients with lung injury caused by paraquat poisoning. The receiver operating characteristics (ROC) curve was used to analyze the diagnostic value of serum IL-6, sIL-6R and sgp130 on paraquat poisoning-induced lung injury.Results:The serum levels of IL-6, sIL-6R, and sgp130 in the observation group were significantly higher than those in the control group: (108.62 ± 11.39) ng/L vs. (57.41 ± 7.63) ng/L, (73.28 ± 6.94) ng/L vs. (45.13 ± 6.57) ng/L, (435.64 ± 36.52) mg/L vs. (281.71 ± 68.35) mg/L, and the differences were statistically significant ( P<0.05). The results of correlation analysis showed that the serum levels of IL-6, sIL-6R, and sgp130 in the observation group were significantly positively correlated with the APACHE-Ⅱ score ( r = 0.824, 0.937, 1.215, P<0.05). ROC curve analysis results showed that when serum IL-6, sIL-6R and sgp130 had the best diagnostic cut-off values of 83.96 ng/L, 68.51 ng/L and 367.42 mg/L respectively for the lung injury caused by paraquat poisoning, the sensitivity was 84.80%, 78.20% and 87.10%, and the specificity was 70.30%, 85.50% and 81.00%. Conclusions:The expression levels of IL-6, sIL-6R and sgp130 in serum are closely related to the severity of lung injury caused by paraquat poisoning, and IL-6, sIL-6R and sgp130 have good diagnostic value in lung injury caused by paraquat poisoning.

Associations between the IL-6-neutralizing sIL-6R-sgp130 buffer system and coronary artery disease in postmenopausal women.

BACKGROUND: As a major inflammatory pathway in coronary artery disease (CAD), IL-6 trans-signaling is activated by the IL-6: sIL-6Rα binary complex (B) and inhibited by sgp130 through forming the IL-6: sIL-6Rα: sgp130 ternary complex (T). The aim of the present study was to examine the possible relationship between biomarkers mirroring the IL-6-neutralizing sIL-6R-sgp130 buffer system and CAD in postmenopausal women. METHODS: Our study recruited 155 CAD patients and 181 controls among postmenopausal women. Circulating levels of IL-6, sIL-6Rα and sgp130 were detected using an enzyme-linked immunosorbent assay, and the B/T ratio was calculated by the specific formulas. RESULTS: CAD patients showed significantly higher circulating levels of IL-6 and sIL-6Rα, significantly higher B/T ratio, and significantly lower sgp130 levels than controls (all P<0.05). Spearman's correlation analysis indicated that IL-6 levels (r=0.185, P<0.01) and B/T ratio (r=0.319, P<0.01) were positively related to Gensini scores, while elevated sgp130 levels were significantly associated with decreased Gensini scores (r=-0.565, P<0.001). In addition, multiple regression analysis showed that Gensini scores were negatively associated with serum sgp130 levels (ß-coefficient =-0.318, P<0.001) and had a positive association with IL-6 levels (ß-coefficient =0.138, P<0.05). Multivariate logistic regression analysis identified that after adjusting for confounding factors, higher sgp130 remained an independent predictor of lower incidence of CAD in women after menopause (OR =0.904; 95% CI: 0.837-0.976, P=0.010). Moreover, sgp130 levels at 136.01 ng/mL (AUC =0.957, 95% CI: 0.928-0.986, P<0.001) and B/T ratio at 1.51 (AUC =0.765; 95% CI: 0.702-0.828, P<0.001) were effective cut-off points to determine the presence of CAD based on receiver operating characteristic curves. CONCLUSIONS: Based on this small case-control study, sgp130 and B/T ratio in the IL-6-neutralizing sIL-6R-sgp130 buffer system may be promising biomarkers for CAD diagnosis and assessments of coronary stenosis severity in postmenopausal women.

Plasma interleukin 6 levels are associated with cardiac function after ST-elevation myocardial infarction.

BACKGROUND AND AIMS: Myocardial infarction triggers an inflammatory response involved in cardiac repair. We studied the association of the interleukin 6 (IL-6) cascade with infarct size and cardiac function after ST-elevation myocardial infarction (STEMI). METHODS: In 369 STEMI patients IL-6, soluble IL-6 receptor (sIL-6R), and soluble glycoprotein (sgp) 130 were measured at baseline (hospital admission), 24 h, 2 weeks, 7 weeks, 4 months, and 1 year post-PCI and sIL-6R/IL-6 ratio was calculated. At 4 months, infarct size and left ventricular ejection fraction (LVEF) were assessed by magnetic resonance imaging. Diastolic function (E/e') was determined by echocardiography. RESULTS: Hospital admission levels for IL-6, sIL-6R, sgp 130 were 3.7 pg/ml (IQR 2.1-6.7 pg/ml), 51.6 ng/ml (IQR 37.3-69.0 ng/ml), and 332 ng/ml (IQR 280-399 ng/ml), respectively. 24 h after admission, IL-6 had increased threefold compared to baseline (p < 0.001) and returned below baseline (p < 0.001) 2 weeks after STEMI. sIL-6R and sgp130 levels at 24 h remained similar to baseline but were increased at 2 weeks (p < 0.001; p < 0.001, respectively). IL-6 and sIL-6R/IL-6 ratio at 24 h were independently associated with infarct size [ß 5.4 (95% CI 3.3-7.5); p < 0.001, ß - 4.0 (95% CI - 6.1 to - 1.9); p < 0.001, respectively]. Higher levels of IL-6 at 24 h were associated with lower LVEF [ß - 4.2 (95% CI -6.7 to - 1.8); p = 0.001]. CONCLUSIONS: Higher IL-6 and lower sIL-6R/IL-6 ratio early after presentation with STEMI are indicative for larger infarct size and decreased cardiac function at 4 months.

Soluble glycoprotein 130 is inversely related to severity of coronary atherosclerosis.

PURPOSE: Recent studies indicate that the effects of interleukin 6 (IL-6) realized via soluble IL-6 receptor (sIL-6R) facilitate the development of various pathological processes. Soluble gp130 (sgp130) is a naturally occurring inhibitor of signal transduction via this pathway. In this study, we assessed the relationship between circulating levels of IL-6, sIL-6R and sgp130 and severity of coronary atherosclerosis in patients with stable coronary artery disease (CAD). METHODS: Plasma levels of IL-6, sIL-6R and sgp130 were measured in patients with atherosclerotic coronary lesions (n = 128, group 1) and with intact coronary arteries (n = 48, group 2). The severity of coronary atherosclerosis was evaluated by the number of affected arteries and by Gensini Score index. RESULTS: Circulating IL-6 levels in group 1 were significantly higher than those in group 2. The levels of sIL-6R did not differ considerably in both the groups. The levels of sgp130 in group 1 were significantly lower than in group 2. A negative correlation has been revealed between sgp130 levels and the number of affected coronary arteries and Gensini Score index. CONCLUSIONS: Serum concentration of sgp130 in patients with stable CAD is inversely related to severity of coronary damage. Low sgp130 level may serve as an additional indicator of coronary atherosclerosis severity.

Interleukin-6 signaling in patients with chronic heart failure treated with cardiac resynchronization therapy.

INTRODUCTION: Increased expression of interleukin-6 (IL-6) has been described in left ventricular dysfunction in the course of chronic heart failure. Cardiac resynchronization therapy (CRT) is a unique treatment method that may reverse the course of chronic heart failure (CHF) with reduced ejection fraction (HF-REF). We aimed to evaluate the IL-6 system, including soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (sgp130), in HF-REF patients, with particular emphasis on CRT effects. MATERIAL AND METHODS: The study enrolled 88 stable HF-REF patients (63.6 ±11.1 years, 12 females, EF < 35%) and 35 comorbidity-matched controls (63.5 ±9.8 years, 7 females). Forty-five HF-REF patients underwent CRT device implantation and were followed up after 6 months. Serum concentrations of IL-6, sIL-6R and sgp130 were determined using ELISA kits. RESULTS: The HF-REF patients had higher IL-6 (median: 2.6, IQR: 1.6-3.8 vs. 2.1, IQR: 1.4-3.1 pg/ml, p = 0.03) and lower sIL-6R concentrations compared to controls (median: 51, IQR: 36-64 vs. 53. IQR 44-76 ng/ml, p = 0.008). There was no significant difference between sgp130 concentrations. In the HF-REF group IL-6 correlated negatively with EF (r = -0.5, p = 0.001) and positively with BNP (r = 0.5, p = 0.008) and CRP concentrations (r = 0.4, p = 0.02). Patients who presented a positive response after CRT showed a smaller change of sIL-6R concentration compared to nonresponders (ΔsIL-6R: -0.2 ±7.1 vs. 7 ±14 ng/ml; p = 0.04). CONCLUSIONS: HF-REF patients present higher IL-6 and lower sIL-6R levels. IL-6 concentration reflects their clinical status. CRT-related improvement of patients' functional status is associated with a smaller change of sIL-6R concentration in time.

Soluble Glycoprotein 130 and Heat Shock Protein 27 as Novel Candidate Biomarkers of Chronic Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Despite their importance, the current clinical biomarkers of chronic heart failure have limitations. In this study, soluble glycoprotein 130 (sgp130), heat shock protein 27 (hsp27), dipeptidyl peptidase IV (dpp4) and cathepsin S (CTSS) were tested for their potential as novel biomarkers for diagnosing chronic heart failure (CHF) with preserved ejection fraction. METHODS: We compared the circulating levels of sgp130, hsp27, dpp4, and cathepsin S in patients with CHF with preserved ejection fraction (n=50) and in controls (n=50), determined how well these candidate biomarkers distinguish patients with CHF from controls, and assessed whether these candidates are superior to N-terminal pro brain natriuretic peptide (NT-pro-BNP) as diagnostic tools. RESULTS: After adjusting for clinical covariates, patients with CHF showed significantly higher mean concentrations of sgp130 (317.38pg/ml vs. 215.90 pg/ml), hsp27 (2601.02 pg/ml vs. 923.61 pg/ml) and NT-pro-BNP (982.35 pg/ml vs. 331.99 pg/ml), but not dpp4 (6930.9 4pg/ml vs. 7081.37 pg/ml) or CTSS (1050.46 pg/ml vs. 984.96 pg/ml), than did controls. In the receiver operating characteristic curve analysis, hsp27 showed the most notable difference between CHF patients and controls, with the largest area under the curve (AUC) (0.920); the AUC values for sgp130 and NT-pro-BNP were 0.877 and 0.882, respectively. CONCLUSIONS: Soluble glycoprotein 130 and hsp27 are novel candidate biomarkers for diagnosing CHF with preserved ejection fraction and thus warrant further investigation; neither dpp4 nor CTSS showed promise as biomarkers of CHF.

Effects of diet and/or n-3 fatty acid supplementation on components of the interleukin-6 trans-signalling system in elderly men.

BACKGROUND: It has previously been shown that both very long chain omega-3 polyunsaturated fatty acids (n-3 PUFA) and a Mediterranean-like diet (Md), are able to reduce the risk of cardiovascular (CV) mortality and morbidity. The exact mechanisms behind this effect are yet to be established. To date, there exist no data on the effect of n-3 PUFA supplementation and Md on components of the interleukin-6 (IL-6) trans-signalling (ts) system that plays a central role in the family of pro-atherosclerotic inflammatory markers. METHODS: A total of 563 men were included in the DOIT study, a randomised factorial-designed trial comparing the effect of 36 months of dietary counseling, n-3 PUFA supplementation (2.4 g/d), or both on different circulating biomarkers of atherosclerosis in elderly high-risk men. We used commercially available ELISA methods to analyse circulating levels of soluble glycoprotein 130 (sGP130), soluble IL-6 receptor (sIL-6r), and IL-6. RESULTS: There was no significant effect of either of the intervention principles on circulating levels of sGP130 or sIL-6r. We have shown previously that there is no effect on IL-6 concentrations either. CONCLUSIONS: This is the largest trial analysing possible effects of Md or n-3 PUFA supplementation on the IL-6ts system. Although the reduction of CV risk through dietary intervention or n-3 PUFA supplementation has previously been linked to anti-inflammatory effects, we could not find an effect of these interventions on the IL-6ts system. This indicates that the beneficial effects of Md or n-3 PUFA observed in previous studies seem to be independent of the IL-6ts system.

IL-6 signalling in patients with acute ST-elevation myocardial infarction.

Cytokines of the IL-6 family have been related to infarct size and prognosis in patients with myocardial infarction. The aims of the present study were to elucidate possible associations between myocardial necrosis and left ventricular impairment and members of the IL-6 transsignalling system including soluble (s) IL-6R and (s) glycoprotein 130 (sgp130) in patients with ST-elevation myocardial infarction (STEMI) treated with primary PCI. In blood samples from 1028 STEMI patients, collected in-hosptial, we found significant correlations between peak TnT and IL-6 and CRP (p < 0.001, all) and between IL-6 and CRP and LV ejection fraction and NT-proBNP (p < 0.001, all). On the contrary, no significant associations were found between peak TnT and sgp130 or sIL-6R. Furthermore sgp130 was significantly elevated in diabetic patients and also associated with the glucometabolic state. In conclusion, circulating levels of IL-6 and CRP, but not the soluble forms of the receptor (sIL-6R) or the receptor signalling subunit (sgp130) were associated with the extent of myocardial necrosis. The biological importance of the IL-6/gp130-mediated signalling pathways in patients with acute myocardial infarction and dysglycemia should be further elucidated.