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Circulating proteomes provide a snapshot of the physiological state of a human organism responding to pathogenic challenges and drug interventions. The outcomes of patients with COVID-19 and acute respiratory distress syndrome triggered by the SARS-CoV2 virus remain uncertain. Tocilizumab is an anti-interleukin-6 treatment that exerts encouraging clinical activity by controlling the cytokine storm and improving respiratory distress in patients with COVID-19. We investigate the biological determinants of therapeutic outcomes after tocilizumab treatment. Overall, 28 patients hospitalized due to severe COVID-19 who were treated with tocilizumab intravenously were included in this study. Sera were collected before and after tocilizumab, and the patient's outcome was evaluated until day 30 post-tocilizumab infusion for favorable therapeutic response to tocilizumab and mortality. Hyperreaction monitoring measurements by liquid chromatography-mass spectrometry-based proteomic analysis with data-independent acquisition quantified 510 proteins and 7019 peptides in the serum of patients. Alterations in the serum proteome reflect COVID-19 outcomes in patients treated with tocilizumab. Our results suggested that circulating proteins associated with the most significant prognostic impact belonged to the complement system, platelet degranulation, acute-phase proteins, and the Fc-epsilon receptor signaling pathway. Among these, upregulation of the complement system by activation of the classical pathway was associated with poor response to tocilizumab, and upregulation of Fc-epsilon receptor signaling was associated with lower mortality.

Background: Interleukin (IL)-6 is a major inflammatory cytokine that predicts mortality after out-of-hospital cardiac arrest (OHCA). Targeted temperature management (TTM) is associated with improved all-cause mortality in patients with OHCA. However, the effect of TTM on IL-6 production remains unclear. This study investigated whether TTM has additional anti-inflammatory effects after OHCA., Methods: This prospective cohort study included a total of 141 hospitalized patients with OHCA who were treated between January 2015 and June 2023. The study was conducted in the intensive care unit of China Medical University Hospital, Taichung. Postcardiac arrest care included TTM or the control approach (no TTM). The primary outcomes included the 90-day mortality rate and neurologic outcomes after OHCA. Differences between the TTM and control groups were examined using Student t test, chi-square test, and Kaplan-Meier survival curve analysis. Multivariate analysis of variance model was used to examine interaction effects., Results: Plasma IL-6 and IL-6/soluble IL-6 receptor complex levels were measured at 6 and 24 hours after resuscitation. IL-6 and IL-6/soluble IL-6 receptor complex production was lower in the TTM group than in the control group (-50.0% vs +136.7%, P < .001; +26.3% vs +102.40%, P < .001, respectively). In addition, the 90-day mortality rate and poor neurologic outcomes were lower in the TTM group than in the control group (36.8% vs 63.0%, relative risk 0.39, 95% confidence interval 0.24-0.64, P < .001; 65.5% vs 81.5%, relative risk 0.80, 95% confidence interval 0.66-0.98, P = .04)., Conclusion: TTM improves both the mortality rate and neurologic outcomes in patients resuscitated from OHCA, possibly by reducing IL-6-induced proinflammatory responses., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Interleukin 6 (IL-6) levels at hospital admission have been suggested for disease prognosis, and IL-6 antagonists have been suggested for the treatment of patients with severe COVID-19. However, less is known about the relationship between pre-COVID-19 IL-6 levels and the risk of severe COVID-19. To fill in this gap, here we extensively investigated the association of genetically instrumented IL-6 pathway components with the risk of severe COVID-19., Methods: We used a two-sample Mendelian randomization study design and retrieved genetic instruments for blood biomarkers of IL-6 activation, including IL-6, soluble IL-6 receptor, IL-6 signal transducer, and CRP, from respective large available GWASs. To establish associations of these instruments with COVID-19 outcomes, we used data from the Host Genetics Initiative and GenOMICC studies., Results: Our analyses revealed inverse associations of genetically instrumented levels of IL-6 and its soluble receptor with the risk of developing severe disease (OR = 0.60 and 0.94, respectively). They also demonstrated a positive association of severe disease with the soluble signal transducer level (OR = 1.13). Only IL-6 associations with severe COVID-19 outcomes reached the significance threshold corrected for multiple testing ( p < 0.003; with COVID-19 hospitalization and critical illness)., Conclusions: These potential causal relationships for pre-COVID-19 IL-6 levels with the risk of developing severe symptoms provide opportunities for further evaluation of these factors as prognostic/preventive markers of severe COVID-19. Further studies will need to clarify whether the higher risk for a severe disease course with lower baseline IL-6 levels may also extend to other infectious diseases.

Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6-mediated inflammation., Competing Interests: Conflict of interest K. M., M. W. S., A. B., P. B., G. P. G., and S. F. are employees of and stockholders in Regeneron Pharmaceuticals, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Specific features of IL-6 signal transduction were studied in 89 patients with lung damage of varying degrees during the first COVID-19 pandemic wave. The levels of IL-6 signaling components (IL-6, sIL-6R, and sgp130) and highly sensitive C-reactive protein (hsCRP) were examined in patients with intact lungs (CT-0), mild (CT-1), moderate (CT-2), moderate to severe (CT-3), and severe (CT-4) lung damage. Seventy patients were re-examined 3-7 months after discharge from the hospital. The IL-6 and hsCRP levels increased several times with severing lung damage severity. In patients with CT-3, sIL6-R increased statistically significantly and remained high in CT-4 patients. sgp130 levels were lower in CT-1 and CT-2 patients and higher in CT-3 and CT-4 patients compared to CT-0 patients. We revealed a positive correlation between IL-6 and hsCRP levels in CT-1, CT-2, and CT-3 patients. In CT-3 patients, sIL-6R levels positively correlated with IL-6 concentration. The studied parameters decreased considerably in all patients 3-7 months after discharge. It can be suggested that IL-6 classic-signaling is predominant in CT-1 and CT-2, while trans-signaling prevails in CT-3. Disorders in regulatory mechanisms of IL-6 signaling occur in CT-4, which prevents physiological elimination of IL-6 hyperactivity. The results obtained are preliminary and require a broader study., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Studies investigating the association between IL-6/IL-6R axis and schizophrenia (SZ) susceptibility found inconsistent data. To reconcile the results, a systematic review followed by a meta-analysis was performed to assess the associations. This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive search of the literature was carried out in July 2022 using electronic databases PubMed, EBSCO, Science Direct, PsychInfo, and Scopus. Study quality was assessed by the Newcastle-Ottawa scale. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed-effect or random-effect model analysis. Fifty-eight studies were identified, including 4,200 SZ patients and 4,531 controls. Our meta-analysis results showed an increase of IL-6 levels in plasma, serum, or CSF and decreased IL-6R levels in serum in patients under treatment. Further studies are needed to better elucidate the correlation between the IL-6/IL-6R axis and the schizophrenia., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Alzheimer disease (AD) is a neurodegenerative disease process manifesting clinically with cognitive impairment and dementia. AD pathology is complex, and in addition to plaques and tangles, neuroinflammation is a consistent feature. Interleukin (IL) 6 is a multifaceted cytokine involved in a plethora of cellular mechanisms including both anti-inflammatory and inflammatory processes. IL6 can signal classically through the membrane-bound receptor or by IL6 trans-signaling forming a complex with the soluble IL6 receptor (sIL6R) and activating membrane-bound glycoprotein 130 on cells not expressing IL6R. IL6 trans-signaling has been demonstrated as the primary mechanism of IL6-mediated events in neurodegenerative processes. In this study, we performed a cross-sectional analysis to investigate whether inheritance of a genetic variation in the IL6R gene and associated elevated sIL6R levels in plasma and CSF were associated with cognitive performance., Methods: We genotyped the IL6R rs2228145 nonsynonymous variant (Asp 358 Ala) and assayed IL6 and sIL6R concentrations in paired samples of plasma and CSF obtained from 120 participants with normal cognition, mild cognitive impairment, or probable AD enrolled in the Wake Forest Alzheimer's Disease Research Center's Clinical Core. IL6 rs2228145 genotype and measures of plasma IL6 and sIL6R were assessed for relationships with cognitive status and clinical data, including the Montreal Cognitive Assessment (MoCA), modified Preclinical Alzheimer's Cognitive Composite (mPACC), cognitive domain scores obtained from the Uniform Data Set, and CSF concentrations of phosphoTau T181 (pTau181), β-amyloid (Aβ) Aβ40 and Aβ42 concentrations., Results: We found that inheritance of the IL6R Ala 358 variant and elevated sIL6R levels in plasma and CSF were correlated with lower mPACC, MoCA and memory domain scores, increases in CSF pTau181, and decreases in the CSF Aβ42/40 ratio in both unadjusted and covariate-adjusted statistical models., Discussion: These data suggest that IL6 trans-signaling and the inheritance of the IL6R Ala 358 variant are related to reduced cognition and greater levels of biomarkers for AD disease pathology. Follow-up prospective studies are necessary, as patients who inherit IL6R Ala 358 may be identified as ideally responsive to IL6 receptor-blocking therapies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Preoperative plasma levels of Interleukin 6 (IL6) and its soluble receptor (IL6sR) have previously been associated with oncologic outcomes in urothelial carcinoma of the bladder (UCB); however, external validation in patients treated with radical cystectomy (RC) for UCB is missing., Patients/methods: We prospectively collected preoperative plasma from 1,036 consecutive patients at two institutes. These plasma specimens were assessed for levels of IL6 and IL6sR. Logistic and Cox regression analyses were used to assess the correlation of plasma levels with pathologic and survival outcomes. The additional clinical net benefits of preoperative IL6 and IL6sR were evaluated using decision curve analysis (DCA)., Results: Median IL6 and IL6sR plasma levels were significantly higher in patients with adverse pathologic features. Elevated biomarker levels were independently associated with an increased risk for lymph node metastasis and ≥ pT3 disease. Both biomarkers were independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The addition to, respectively, fitted pre- and postoperative prognostic models improved the predictive accuracy for lymph node metastasis, ≥ pT3 disease, RFS and CSS on DCA., Interpretation: We confirmed that elevated preoperative plasma levels of IL6 and IL6sR levels are associated with worse oncological disease survival in patients treated with RC for UCB in a large multicenter study. Both biomarkers hold potential in identifying patients with adverse pathological features that may benefit from intensified/multimodal therapy and warrant inclusion into predictive/prognostic models. They demonstrated the ability to improve the discriminatory power of such models and thus guide clinical decision making., (© 2021. The Author(s).)

Purpose: Obstructive sleep apnea (OSA) results in systemic intermittent hypoxia. By one model, hypoxic stress signaling in OSA patients alters the levels of inflammatory soluble cytokines TNF and IL6, damages the blood brain barrier, and activates microglial targeting of neuronal cell death to increase the risk of neurodegenerative disorders and other diseases. However, it is not yet clear if OSA significantly alters the levels of the soluble isoforms of TNF receptors TNFR1 and TNFR2 and IL6 receptor (IL6R) and co-receptor gp130, which have the potential to modulate TNF and IL6 signaling., Methods: Picogram per milliliter levels of the soluble isoforms of these four cytokine receptors were estimated in OSA patients, in OSA patients receiving airways therapy, and in healthy control subjects. Triplicate samples were examined using Bio-Plex fluorescent bead microfluidic technology. The statistical significance of cytokine data was estimated using the nonparametric Wilcoxon rank-sum test. The clustering of these high-dimensional data was visualized using t-distributed stochastic neighbor embedding (t-SNE)., Results: OSA patients had significant twofold to sevenfold reductions in the soluble serum isoforms of all four cytokine receptors, gp130, IL6R, TNFR1, and TNFR2, as compared with control individuals (p = 1.8 × 10 -13 to 4 × 10 -8 ). Relative to untreated OSA patients, airways therapy of OSA patients had significantly higher levels of gp130 (p = 2.8 × 10 -13 ), IL6R (p = 1.1 × 10 -9 ), TNFR1 (p = 2.5 × 10 -10 ), and TNFR2 (p = 5.7 × 10 -9 ), levels indistinguishable from controls (p = 0.29 to 0.95). The data for most airway-treated patients clustered with healthy controls, but the data for a few airway-treated patients clustered with apneic patients., Conclusions: Patients with OSA have aberrantly low levels of four soluble cytokine receptors associated with neurodegenerative disease, gp130, IL6R, TNFR1, and TNFR2. Most OSA patients receiving airways therapy have receptor levels indistinguishable from healthy controls, suggesting a chronic intermittent hypoxia may be one of the factors contributing to low receptor levels in untreated OSA patients., (© 2020. The Author(s).)

IL-6 has been suggested to function as an autocrine mitogen in the psoriatic epidermis. The biological activity of IL-6 relies on interactions with its receptors, including the membrane-bound IL-6 receptor (mIL-6R) and soluble IL-6 receptor (sIL-6R). Our study presents data showing that the levels of plasma IL-6 and sIL-6R were elevated in psoriatic patients. Genotyping of two single-nucleotide polymorphisms (SNPs) in IL-6R (rs4845617 and rs2228145) demonstrated that the SNP IL-6R (rs4845617) rather than IL-6R (rs2228145) shows a significant association with psoriasis (P = 0.006). To verify the functions of sIL-6R, cultured keratinocytes and imiquimod (IMQ)-induced psoriatic model mice were treated with sIL-6R. We found that the presence of sIL-6R in the HaCaT cell culture medium enhanced the IL-6-induced Stat3 activation, which resulted in abnormal keratinocyte proliferation and aberrant differentiation. Furthermore, the application of sIL-6R in vivo accelerated the pathological development of the disease. Our results demonstrate for the first time that genetic polymorphisms in the IL-6R gene are associated with psoriasis disease phenotypes in a Chinese psoriatic patient population; sIL-6R-mediated trans-signaling pathway plays a pivotal role in keratinocyte proliferation and differentiation, suggesting potential therapeutics for psoriasis. KEY MESSAGES: Patients with psoriasis displayed higher levels of IL-6 and sIL-6R compared with healthy controls. Analysis of genotypes revealed that IL-6R rs4845617 GG genotype associated with the risk of psoriasis. Supplement of sIL-6R further enhanced IL-6-induced Stat3 activation in keratinocytes. In vivo administration of sIL-6R accelerated, whereas sgp130FC alleviated, the pathological development of psoriasis.

This study builds a coronavirus knowledge graph (KG) by merging two information sources. The first source is Analytical Graph (AG), which integrates more than 20 different public datasets related to drug discovery. The second source is CORD-19, a collection of published scientific articles related to COVID-19. We combined both chemo genomic entities in AG with entities extracted from CORD-19 to expand knowledge in the COVID-19 domain. Before populating KG with those entities, we perform entity disambiguation on CORD-19 collections using Wikidata. Our newly built KG contains at least 21,700 genes, 2500 diseases, 94,000 phenotypes, and other biological entities (e.g., compound, species, and cell lines). We define 27 relationship types and use them to label each edge in our KG. This research presents two cases to evaluate the KG's usability: analyzing a subgraph (ego-centered network) from the angiotensin-converting enzyme (ACE) and revealing paths between biological entities (hydroxychloroquine and IL-6 receptor; chloroquine and STAT1). The ego-centered network captured information related to COVID-19. We also found significant COVID-19-related information in top-ranked paths with a depth of three based on our path evaluation.

Background: The Nod-Like-Receptor-Protein-3 (NLRP3) inflammasome and the Interleukin-6 (IL-6) pathways are central mechanisms of the inflammatory response in myocardial reperfusion injury. Expanding our knowledge about the inflammasome signaling axis is important to improve treatment options. In a cross-sectional study, we aimed to study presence, localization, and genetic expression of inflammasome- and IL-6- signaling-related proteins in coronary thrombi and circulating leukocytes from ST-elevation myocardial infarction (STEMI) patients, with relation to myocardial injury and time from symptoms to PCI., Methods: Intracoronary thrombi were aspirated from 33 STEMI patients. Blood samples were drawn. mRNA of Toll-Like-Receptor-4 (TLR4), NLRP3, caspase 1, Interleukin-1 β (IL1- β ), Interleukin-18 (IL-18), IL-6, IL-6-receptor (IL-6R), and glycoprotein 130 (gp130) were isolated from thrombi and circulating leukocytes and relatively quantified by RT-PCR. A part of each thrombus was embedded in paraffin for histology and immunohistochemistry analyses., Results: Genes encoding the 8 markers were present in 76-100% of thrombi. Expression of TLR4 in thrombi significantly correlated to troponin T ( r = 0.455, p = 0.013), as did NLRP3 ( r = 0.468, p = 0.024). Troponin T correlated with expression in circulating leukocytes of TLR4 ( r = 0.438, p = 0.011), NLRP3 ( r = 0.420, p = 0.0149), and IL-1 β ( r = 0.394, p = 0.023). IL-6R expression in thrombi correlated significantly to troponin T ( r = 0.434, p = 0.019), whereas gp130 was inversely correlated ( r = -0.398, p = 0.050). IL-6 in circulating leukocytes correlated inversely to troponin T ( r = -0.421, p = 0.015). There were no significant correlations between genes expressed in thrombi and time from symptom to PCI., Conclusions: The inflammasome signaling pathway was actively regulated in coronary thrombi and in circulating leukocytes from patients with STEMI, in association with myocardial damage measured by troponin T. This supports the strategy of medically targeting this pathway in treating myocardial infarction and contributes to sort out optimal timing and targets for anti-inflammatory treatment. The study is registered at clinicaltrials.gov with identification number NCT02746822., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Jostein Nordeng et al.)

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Interleukin 6 (IL-6) and its receptors are expressed in approximately half of breast cancer (BC) tissues, and high serum IL-6 levels are associated with poor prognosis. African American (AA) patients with BC have higher serum IL-6 levels compared to Caucasians, suggesting additional risk of disease-related complications in AAs. The purpose of this study was to compare IL-6 complex biomarkers in AA women with and without a history of BC. We conducted a secondary analysis of phenotypic data from two studies of weight loss in AA women with and without a history of BC who had similar age and adiposity. Biomarkers analyzed included tumor necrosis factor alpha (TNF-α), IL-6, IL-6 soluble receptor (IL6sr), and soluble glycoprotein 130 (GP130); IL6sr and GP130 were newly analyzed for this study. TNF-α levels were 1.86 times higher in the BC group (N = 7) compared to those without BC (N = 10; p < 0.001) despite similar age, weight, and body mass index. GP130 levels tended to be higher in women with BC; IL-6 and Il-6 sr were not different between groups. There was a strong correlation between GP130 and TNF-α (r = .638; p = .006) in the group overall. High TNF-α levels in the BC group and a strong correlation between GP130 and TNF-α in the overall group suggest the presence of IL-6 complex initiated TNF-α production. Further study is needed to evaluate IL-6 reduction through a variety of approaches, including weight loss and anti-IL-6 therapies, which may ultimately implicate the reduction of IL-6 complex associated BC-specific recurrence and mortality.

Tocilizumab (TCZ), a humanized monoclonal antibody targeting the interleukin-6 receptor, holds the potential for treating coronavirus disease 2019 (COVID-19) patients, particularly those at high risk of cytokine storm syndrome. However, data regarding the clinical impact of treatment with TCZ in patients with COVID-19 are limited. This study was conducted to evaluate the safety and effectiveness of TCZ as an adjunct therapy for the treatment of severe COVID-19 infection. This was a retrospective observational chart review of confirmed COVID-19 patients who received TCZ, along with other COVID-19 therapies. The outcomes of interest included changes in vital signs such as temperature and laboratory biomarkers, duration of mechanical ventilation, adverse events possibly associated with TCZ, and intensive care unit and hospital lengths of stay. This study included 38 patients with an average age of 63 years (IQR, 48-70 years). The average dose of TCZ given was 519 ± 61 mg. Median C-reactive protein significantly decreased following TCZ administration (189.9 vs 54.8 mg/L, P = .003). Nineteen of all febrile patients before the initiation of TCZ (73%) became fever free on the fourth day of TCZ treatment. Following TCZ treatment, 11 patients developed infections because of multidrug-resistant bacteria, and elevated liver transaminases were observed in 6 patients. The preliminary findings of this study suggested TCZ appeared to ameliorate COVID-19-related cytokine storm syndrome. However, large randomized, controlled trials are needed to investigate whether treatment with TCZ is associated with better outcomes in COVID-19., (© 2020, The American College of Clinical Pharmacology.)

The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Interleukin (IL) 6 contributes to atherosclerotic plaque development through IL6 membrane-bound (IL6R and gp130) and soluble (sIL6R and sgp130) receptors. We investigated IL6 receptor expression in carotid plaques and its correlation with circulating IL6 and soluble receptor levels. Plasma samples and carotid plaques were obtained from 78 patients in the Biobank of Karolinska Endarterectomies study. IL6, sIL6R, and sgp130 were measured in plasma and IL6, IL6R, sIL6R, GP130 , and s GP130-RAPS (s GP130 ) gene expression assessed in carotid plaques. Correlations between plaque IL6 signaling gene expression and plasma levels were determined by Spearman's correlation. Differences in plasma and gene expression levels between patients with ( n = 53) and without ( n = 25) a history of a cerebral event and statin-treated ( n = 65) and non-treated ( n = 11), were estimated by Kruskal-Wallis. IL6 and its receptors were all expressed in carotid plaques. There was a positive, borderline significant, moderate correlation between plasma IL6 and sIL6R and the respective gene expression levels (rho 0.23 and 0.22, both p = 0.05). IL6R expression was higher in patients with a history of a cerebrovascular event compared to those without ( p = 0.007). Statin-treated had higher IL6R, sIL6R , and s GP130 expression levels and plasma sIL6R compared to non-treated patients (all p < 0.05). In conclusion, all components of the IL6 signaling pathways are expressed in carotid artery plaques and IL6 and sIL6R plasma levels correlate moderately with IL6 and sIL6R . Our data suggest that IL6 signaling in the circulation might mirror the system activity in the plaque, thus adding novel perspectives to the role of IL6 signaling in atherosclerosis.

Introduction: High-intensity interval training (HIIT) is considered a time-efficient strategy to improve metabolic health. We performed a systematic meta-analysis to assess the effects of HIIT on inflammatory markers and adipo-cytokines compared with control conditions (CON) or moderate-intensity continuous training (MICT) in individuals with metabolic disorders., Methods: Up to January 2020, electronic databases were searched for HIIT interventions based on populations with metabolic disorders including diabetes, metabolic syndrome, polycystic ovary syndrome, non-alcoholic fatty liver disease or overweight/obesity, with outcome measurements that included IL-6, TNF-α, CRP, leptin or adiponectin and training ≥2 weeks. Random-effects models were used to aggregate a mean effect size (ES), 95% confidence intervals (Cis), and potential moderators were explored., Results: Twenty-nine studies involving 841 participants were included in the meta-analysis. HIIT improved circulating adiponectin (P = .02), leptin (P = .02), and TNF-α (P = .003) when compared to CON. There were no differences between groups in IL-6 and CRP. Intervention duration was a significant moderator for the effect of HIIT on IL-6, and leptin (P < .05)., Conclusion: High-intensity interval training improves circulating TNF-α, leptin and adiponectin, thereby indicating that it may be an effective and time-efficient intervention for controlling low-grade inflammation in individuals with metabolic disorders., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Biliary tract cancer (BTC) is a heterogeneous group of rare gastrointestinal malignancies with dismal prognosis often associated with inflammation. We assessed the prognostic value of IL6 and YKL-40 compared with CA19-9 before and during palliative chemotherapy. We also investigated in mice whether IL6R inhibition in combination with gemcitabine could prolong chemosensitivity., Experimental Design: A total of 452 Danish participants with advanced (locally advanced and metastatic) BTC were included from six clinical trials (February 2004 to March 2017). Serum CA19-9, IL6, and YKL-40 were measured before and during palliative treatment. Associations between candidate biomarkers and progression-free survival (PFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression. Effects of inhibiting IL6R and YKL-40 were assessed in vitro , and of IL6R inhibition in vivo ., Results: High pretreatment levels of CA19-9, IL6, and YKL-40, and increasing levels during treatment, were associated with short PFS and OS in patients with advanced BTC. IL6 provided independent prognostic information, independent of tumor location and in patients with normal serum CA19-9. ROC analyses showed that IL6 and YKL-40 were predictive of very short OS (OS < 6 months), whereas CA19-9 was best to predict OS > 1.5 years. Treatment with anti-IL6R and gemcitabine significantly diminished tumor growth when compared with gemcitabine monotherapy in an in vivo transplant model of BTC., Conclusions: Serum IL6 and YKL-40 are potential new prognostic biomarkers in BTC. IL6 provides independent prognostic information and may be superior to CA19-9 in certain contexts. Moreover, anti-IL6R should be considered as a new treatment option to sustain gemcitabine response in patients with BTC., (©2020 American Association for Cancer Research.)

Aim: A substantial proportion of major depressive disorder patients are treatment-resistant to antidepressant therapy, who require augmentation drugs, or other treatments including electroconvulsive therapy or transcranial magnetic stimulation. Identifying treatment-resistant major depressive disorder patients before the actual administration of antidepressant is, however, often difficult. Accordingly, the serum biomarker to identify treatment-resistant patients will be helpful in clinical settings. This study aims to clarify the appropriate biomarkers for identification of treatment-resistant major depressive disorder., Method: Given that immune-inflammatory processes are involved in the pathogenesis of major depressive disorder, it is possible that certain cytokine-related molecules could serve as clinically useful biomarkers of treatment-resistant major depressive disorder patients. In this study, we measured serum levels of tumor necrosis factor-α, interleukin 6, and soluble interleukin 6 receptor after major depressive disorder patients underwent antidepressant therapy., Results: The serum level of soluble interleukin 6 receptor, but not interleukin 6 or tumor necrosis factor-α, was significantly higher in treatment-resistant major depressive disorder patients than in remitted patients, suggesting that serum soluble interleukin 6 receptor could be a good biomarker of treatment-resistant major depressive disorder. Receiver operating characteristic analysis confirmed that serum soluble interleukin-6 receptor level measurement was useful for identification of treatment-resistant major depressive disorder patients. Multiple regression analysis using the serum levels of the aforementioned cytokines as explanatory variables and the Quick Inventory of Depressive Symptomatology-Self Report score (QIDS-SR 16 ) as a target variable showed that only serum soluble interleukin-6 receptor level could explain the severity of major depressive disorder., Conclusion: Based on these results, we recommend measurement of serum soluble interleukin-6 receptor level to discriminate treatment-resistant major depressive disorder patients. High serum soluble interleukin-6 receptor level is associated with the pathogenesis of treatment-resistant major depressive disorder, suggesting the involvement of the interleukin 6 trans-signaling system in onset of treatment-resistant major depressive disorder., (© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology.)

Introduction: An increased perception of effort and subjective fatigue are thought to be central to decreased exercise performance observed after disrupted sleep. However, there is limited understanding of mechanisms that underpin these phenomena. We investigated the role of interleukin-6 (IL-6), the soluble IL-6 receptor, and neuroendocrine factors (cortisol, adrenaline, noradrenaline, and brain-derived neurotropic factor) in mediating these responses at rest and during exercise., Methods: In a randomized order, 10 healthy active men completed three experimental trials following different sleep conditions: a single night of sleep deprivation, partial sleep deprivation equivalent to 4 h of sleep, and normal sleep. The experimental sessions consisted of physiological and perceptual measurements of exercise intensity throughout 45-min moderate intensity and 15-min maximal effort cycling. Cytokine and neuroendocrine factors were assessed at rest and in response to exercise., Results: Sleep deprivation resulted in increased resting IL-6, lower blood glucose, increased perceived fatigue and perception of effort, lower free-living energy expenditure, and reduced maximal exercise performance. In contrast, sleep deprivation did not alter physiological, cytokine, or neuroendocrine responses to exercise. Variations in the resting concentration of IL-6 were associated with lowered blood glucose, an increased perception of effort, and impaired exercise performance. Resting concentrations of cortisol, adrenaline, noradrenaline, and BNDF showed subtle interactions with specific aspects of mood status and performance but were not affected by sleep deprivation. There were minimal effects of partial sleep deprivation., Conclusions: These findings demonstrate that cytokine and neuroendocrine responses to exercise are not altered by sleep deprivation but that changes in the resting concentration of IL-6 may play a role in altered perception of effort in this context.

Autism spectrum disorder (ASD) is a heterogeneous syndrome characterized by dysregulations in speech and social interactions as well as repetitive and stereotypical behavioral patterns in which immune system plays a significant role. IL-6, an essential cytokine for polarization of Th0 cells into Th17 cells has been demonstrated to be crucial in the etiology of ASD in past studies both in humans and mice. Th17 cells are also believed to be central players in the pathogenesis of ASD through release of IL-17A. However, there is still insufficient data regarding identification of Th17 cells with respect to IL-6 signaling in ASD subjects. Therefore, this study explored IL-6 receptors (IL-6R/sIL-6R) and Th17 (p-STAT3/IL-17A/IL-23R) related markers comprehensively in the blood of typically-developing control (TDC, n = 35) and ASD children (n = 45). Our data show that there is enhanced sIL-6R levels in plasma and CD4+ T cells of ASD subjects as compared to TDC group. Increased sIL-6R signaling is associated with upregulated Th17 development in ASD subjects. Further, severe ASD subjects have higher inflammation in terms of IL-6/IL-17A related signaling as compared to moderate ASD patients. Furthermore, treatment of CD4 + T cells in vitro with IL-6 leads to much greater upregulation of p-STAT3, and IL-17A in ASD subjects than similarly treated CD4+ T cells in TDC group. Antagonism of IL-6 signaling by SC144 in vitro led to blockade of IL-6 mediated effects on CD4+ T cells. These data display unequivocally that IL-6 signaling components are dysregulated which play a crucial in enhancement of Th17 development in ASD subjects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Identification of biomarkers can help monitor and prevent cardiovascular disease (CVD) risk. We performed an exploratory analysis to identify potential biomarkers for coronary heart disease (CHD) in participants from the Life Conditions, Stress, and Health study. A total of 1,007 participants (50% women), randomly selected from the general population, were followed for incident CHD at 8 and 13 years of follow-up. Plasma levels of 184 CVD-related biomarkers were measured in samples collected at baseline in 86 cases with CHD and 184 age- and sex-matched controls by proximity extension assay. Biomarker levels were presented as normalized protein expression values (log 2 scale). After adjusting for confounding factors, 6 biomarkers showed significant association with incident CHD at 13 years. In a sensitivity analysis, this association remained significant at 8 years for 3 biomarkers; collagen α-1(I) chain (COL1A1), bone morphogenetic protein-6 (BMP-6), and interleukin-6 receptor α chain (IL-6Rα). When entering these biomarkers in the full adjustment model simultaneously, their association with incident CHD at 13 years remained significant, hazards ratio being 0.671, 0.335, and 2.854, respectively per unit increase in normalized protein expression values. Subjects with low COL1A1, low BMP-6, and high IL-6Rα levels had a hazards ratio of 5.097 for incident CHD risk (p = 0.019), compared with those without. In conclusion, we identified COL1A1, BMP-6 and IL-6Rα as biomarkers for incident CHD over a long-term follow-up in this exploratory analysis. For COL1A1 and BMP-6 this has not been previously reported. Further studies are needed to confirm our findings and establish their clinical relevance., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Sleep is considered essential for muscle recovery, mainly due to its effect on hormone secretion. Total sleep deprivation or restriction is known to alter not only blood hormones but also cytokines that might be related to skeletal muscle recovery. This study aimed to evaluate whether total sleep deprivation after eccentric exercise-induced muscle damage (EEIMD) modifies the profiles of blood hormones and cytokines., Methods: In two separate conditions, with a crossover and randomized model, 10 men (age, 24.5 ± 2.9 yr; body mass index, 22.7 ± 2.3 kg·m) performed a unilateral EEIMD protocol that comprised 240 eccentric contractions of the knee extensor muscles using an isokinetic dynamometer. In one condition, a "muscle damage" protocol was followed by 48 h of total sleep deprivation and 12 h of normal sleep (DEPRIVATION). In the other condition, the same muscle damage protocol was conducted, followed by three nights of regular sleep (SLEEP). Isometric muscle voluntary contraction tests and blood samples were collected serially throughout the protocol and analyzed for creatine kinase, free and total testosterone, IGF-1, cortisol, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, receptor antagonist of IL-1 and IL-10., Results: Muscle voluntary contraction and serum creatine kinase increased equally over the study period in both conditions. From the cytokines evaluated, only IL-6 increased in DEPRIVATION. No differences were detected in testosterone levels between conditions, but IGF-1, cortisol, and cortisol/total testosterone ratio were higher in DEPRIVATION., Conclusions: Total sleep deprivation after EEIMD does not delay muscle strength recovery but modifies inflammatory and hormonal responses.

Objective: Multiple myeloma (MM) remains an incurable disease that needs better recognition and further research. Previous studies elucidated the interaction between myeloma cells and showed the necessity of bone marrow stromal cells for the initiation and progression of MM. Many chemokines and their receptors including interleukin-8 (IL-8) and soluble interleukin-6 receptor (sIL-6R) play important roles in this interaction. The main purpose of this study is evaluating the serum level of IL-8 and sIL-6R on stage-I of MM patients and healthy controls., Methods: Serum samples from 30 stage-I MM  patients (13 males and 17 females) and 30 healthy subjects as controls (13 males and 17 females) were examined in this study. The protein concentrations of serum IL-8 and sIL-6R were assessed by enzyme-linked immunosorbent assay (ELISA)., Results: The mean level of IL-8 and sIL-6R were significantly elevated in stage-I MM. The mean levels of IL-8 were 1246.57±279.22 ng/ml in stage-I MM and 902.53± 294.61 ng/ml in controls (P<0.001). The mean levels of sIL-6R were 5.39±1.38 ng/ml and 4.1±1.14 ng/ml in stage-I MM and controls, respectively (P<0.001). The mean levels of IL-8 were 1342.18±193.4 ng/ml in patient females and 859± 278.2ng/ml in control females (P <0.001). The mean levels of sIL-6R were 5.21±1.55 ng/ml and 3.91±1.22 ng/ml in patient females and control females, respectively (P=0.01). The mean level of sIL-6R in patient males and control males were 5.63±1.43 ng/ml and 4.34±1.04 ng/ml, respectively (P=0.01). A significant correlation (Pearson's correlation = 0.45, P=0.008) was observed in the population of females (patients and controls)., Conclusion: The results of study suggest the possible involvement of IL-8 and the sIL-6R at stage-I MM and can better characterize the role of chemokines and their receptors in the disease process, especially in the early stages.

Background: Interleukin 6 trans-signalling is independently associated with the risk of cardiovascular events. The aim of this study was to investigate if interleukin 6 trans-signalling can identify individuals at risk for cardiovascular events (coronary artery disease and ischaemic stroke) among those at-low-intermediate risk., Methods: In a cohort of 60-year-olds ( n  = 4232, incident cardiovascular events n  = 525), interleukin 6 trans-signalling was estimated by a ratio between the pro-inflammatory interleukin 6: soluble interleukin 6 receptor binary receptor complex and the inactivated interleukin 6: soluble interleukin 6 receptor: sgp130 ternary complex (B/T ratio). Risk associated with B/T ratio >median was investigated in individuals with low-density lipoprotein cholesterol ≤4.0 (mmol/l) and in those at low-intermediate risk according to the Framingham risk score (FRS) using Cox regression and expressed as hazard ratio and 95% confidence interval. Difference in time to event (years; 95% confidence interval) was analysed with quantile regression. The interaction between low-density lipoprotein cholesterol and B/T ratio was estimated on the additive scale. Incremental discriminatory value of the B/T ratio if low-density lipoprotein cholesterol ≤4.0 was compared to that of the FRS and interleukin 6., Results: B/T ratio >median was associated with increased cardiovascular event risk when low-density lipoprotein cholesterol ≤4.0 (hazard ratio 1.59; 95% confidence interval 1.24-2.05) or FRS ≤ 10%, >10-≤20% (hazard ratio 1.27; 95% confidence interval 1.00-1.61 and hazard ratio 1.78; 95% confidence interval 1.36-2.34, respectively). B/T ratio >median and low-density lipoprotein cholesterol ≤4.0 were associated with early cardiovascular events, particularly ischaemic stroke. No interaction was observed between low-density lipoprotein cholesterol and the B/T ratio, both factors increasing cardiovascular event risk by 60%. In the presence of low-density lipoprotein cholesterol ≤4.0, the B/T ratio slightly improved discrimination measures., Conclusions: Interleukin 6 trans-signalling increases cardiovascular event risk in middle-aged men and women otherwise classified at low-intermediate cardiovascular risk.

Interleukin-6 (IL-6) is critically involved in liver regeneration after partial hepatectomy (PHX). Previous reports suggest that IL-6 trans-signaling through the soluble IL-6/IL-6R complex is involved in this process. However, the long-term contribution of IL-6 trans-signaling for liver regeneration after PHX is unknown. PHX-induced generation of the soluble IL-6R by ADAM (a disintegrin and metallo) proteases enables IL-6 trans-signaling, in which IL-6 forms an agonistic complex with the soluble IL-6 receptor (sIL-6R) to activate all cells expressing the signal-transducing receptor chain glycoprotein 130 (gp130). In contrast, without activation of ADAM proteases, IL-6 in complex with membrane-bound IL-6R and gp130 activates classic signaling. Here, we describe the generation of IL-6 trans-signaling mice, which exhibit boosted IL-6 trans-signaling and abrogated classic signaling by genetic conversion of all membrane-bound IL-6R into sIL-6R proteins phenocopying hyperactivation of ADAM-mediated shedding of IL-6R as single substrate. Importantly, although IL-6R deficient mice were strongly affected by PHX, survival and regeneration of IL-6 trans-signaling mice was indistinguishable from control mice, demonstrating that IL-6 trans-signaling fully compensates for disabled classic signaling in liver regeneration after PHX. Moreover, we monitored the long-term consequences of global IL-6 signaling inhibition versus IL-6 trans-signaling selective blockade after PHX by IL-6 monoclonal antibodies and soluble glycoprotein 130 as fragment crystallizable fusion, respectively. Both global IL-6 blockade and selective inhibition of IL-6 trans-signaling results in a strong decrease of overall survival after PHX, accompanied by decreased signal transducer and activator of transcription 3 phosphorylation and proliferation of hepatocytes. Mechanistically, IL-6 trans-signaling induces hepatocyte growth factor production by hepatic stellate cells. Conclusion: IL-6 trans-signaling, but not classic signaling, controls liver regeneration following PHX., (© 2019 by the American Association for the Study of Liver Diseases.)

Background: The immune system generates inflammatory responses through cytokines like Interleukin 6 (IL-6) and the Tumor Necrosis Factor alpha (TNF α); these cytokines mediate cellular responses aided by the presence of soluble receptors such as: Soluble Interleukin 6 Receptor (sIL6R) and Soluble Tumor Necrosis Factor Receptors Type 1 and 2 (sTNFR1, sTNFR2); the literature is limited about the relationship between this cytokines and the role of its soluble receptors., Objectives: This study is to determine a possible relationship between specific inflammatory markers and their soluble receptors with the autonomic nervous system's activity and body composition., Methods: 27 subjects (13 men of 19.3 ± 1.6 years old and 14 women of 19.1 ± 1.7 years old) were evaluated. Body composition, autonomic nervous system activity and plasma concentration of inflammatory markers IL-6, TNF α, sIL6R, sTNFR1 and sTNFR2 were measured using bio-impedance, heart rate variability and ELISA respectively., Results: A positive association between body-fat percentage and the sIL6R (0.47, p = .013) as well as inverse relationship between muscular mass and the sIL6R (-0.45, p = .019) were found. The sIL6R was also positively correlated with sympathetic activity markers: Relation LF/HF (0.52, p = .006), cardiac sympathetic index (0.45, p = .008), and cardiac vagal index (-0.44, p = .022)., Conclusion: This study suggested that the IL-6 trans-signaling involving both the soluble receptor, sIL6R, and gp130 membrane co-receptor could produce inflammatory responses that generate an impact on the autonomic nervous system, possibly due to its direct action on the hypothalamus, the solitary tract nucleus, or the heart., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

This study compared internal load variable dynamics across three consecutive football matches and investigated its relationship with the number of sprints performed by players. Twenty-three male players had blood and salivary samples collected for hormonal concentration (testosterone, cortisol, and testosterone-cortisol ratio), and serum analysis (interleukin-6, interleukin-1-beta, and c-reactive-protein), respectively. Sprints were measured through Global Position System devices. Testosterone and testosterone-cortisol-ratio presented a decreasing behavior up to the second match, and all other indicators presented an increasing behavior during the same period, c-reactive-protein was the only indicator observed to significantly rise up to the third match as well (0.38±0.02 mg/L; 0.49±0.05 mg/L; 0.69±0.05 mg/L; 0.89±0.08 mg/L). C-reactive-protein showed strong correlations with sprints in the second and third matches (p<0.01, r=0.71 and 0.79), and weak-to-moderate in the first one (p<0.05, r=0.59). Interleukin-6 and interleukin-1-beta presented weak-to-moderate correlation in every match (p<0.05, r=0.48 to 0.51; r=0.51 to 0.55) while testosterone-cortisol ratio presented weak-to-moderate correlation only in the third one (p<0.05, r=0.42). Multilevel linear regression showed that c-reactive-protein had a higher R 2 than other biomarker in any regression model (R2=0.624; p<0.001). Therefore, c-reactive-protein can be a valid and reliable indicator of sprinting in competitive football. Future research should explore longer periods of monitoring and/or others external load variables so that other behaviors may arise to knowledge., Competing Interests: Authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Anal abscess is an important complication of anal fissure (AF), whereas interleukin-6R (IL-6R) has been implicated in the development of abscess. In this study, we aimed to explore the possible molecular mechanisms underlying the regulatory effects of miRNAs on IL-6R and other inflammatory factors related to the induction of anal abscess in AF., Methods: Bioinformatics analysis, luciferase assay, real-time polymerase chain reaction, and Western blot analysis were performed to identify the possible regulatory relationships between IL-6R and miR-124/miR-125a by comparing the differentiated expression of miR-125a, miR-124, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and IL-4 among different groups of AF patients., Results: IL-6R messenger RNA (mRNA) was identified as a target gene of miR-124 because the luciferase activity in cells cotransfected with wild-type IL-6R and miR-124 mimics was significantly reduced. In addition, the expression of IL-6R mRNA and protein was significantly inhibited in the presence of miR-124 or an IL-6R inhibitor, confirming the presence of a negative regulatory relationship between miR-124 and IL-6R. Moreover, miR-124 and inflammatory factors were differentially expressed in AF patients carrying different genotypes of rs531564 polymorphism., Conclusions: miR-124 and inflammatory factors TNF-α, IFN-γ, and IL-4 may be used as indicators of anal abscess development in AF patients. In addition, miR-124 polymorphism rs531564 is involved with the pathogenesis of anal abscess in AF patients, and the presence of rs531564 may increase the incidence of anal abscess via upregulating the expression of IL-6R, TNF-α, IFN-γ, and IL-4., (© 2019 Wiley Periodicals, Inc.)

Immune-mediated diseases (IMDs) arise when tolerance is lost and chronic inflammation is targeted towards healthy tissues. Despite their growing prevalence, therapies to treat IMDs are lacking. Cytokines and their receptors orchestrate inflammatory responses by regulating elaborate signalling networks across multiple cell types making it challenging to pinpoint therapeutically relevant drivers of IMDs. We developed an analytical framework that integrates Mendelian randomization (MR) and multiple-trait colocalization (moloc) analyses to highlight putative cell-specific drivers of IMDs. MR evaluated causal associations between the levels of 10 circulating cytokines and 9 IMDs within human populations. Subsequently, we undertook moloc analyses to assess whether IMD trait, cytokine protein and corresponding gene expression are driven by a shared causal variant. Moreover, we leveraged gene expression data from three separate cell types (monocytes, neutrophils and T cells) to discern whether associations may be attributed to cell type-specific drivers of disease. MR analyses supported a causal role for IL-18 in inflammatory bowel disease (IBD) (P = 1.17 × 10-4) and eczema/dermatitis (P = 2.81 × 10-3), as well as associations between IL-2rα and IL-6R with several other IMDs. Moloc strengthened evidence of a causal association for these results, as well as providing evidence of a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis. In contrast, IL-2rα and IL-6R associations were found to be T cell specific. Our analytical pipeline can help to elucidate putative molecular pathways in the pathogeneses of IMDs, which could be applied to other disease contexts., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This study investigates the relationship between autonomic function and the inflammatory response to a wheelchair half-marathon in people with a spinal cord injury (SCI). Seventeen wheelchair athletes with a cervical SCI (CSCI, N = 7) and without CSCI (NON-CSCI, N = 10) participated in a wheelchair half-marathon. Blood was taken prior, post and 1 h post-race to determine the concentrations of adrenaline, noradrenaline, extracellular heat shock protein 72 (eHsp72) and interleukin-6 (IL-6). A sit-up tilt test was performed to assess autonomic function at rest. CSCI showed a lower supine ratio of the low and high frequency power of the variability in RR intervals (LF/HF RRI, p = 0.038), total and low frequency power of the systolic blood pressure variability (TP SBP, p < 0.001; LF SBP, p = 0.005) compared to NON-CSCI. Following the race, catecholamine concentrations increased only in NON-CSCI ( p < 0.036). The increase in IL-6 post-race was larger in NON-CSCI ( p = 0.040). Post-race catecholamine levels explained 60% of the variance in the IL-6 response ( r = 0.77, p = 0.040), which was further increased when the resting autonomic function indices were added to the regression model (R 2  > 81%, p < 0.012). In summary, the dampened acute inflammatory response to a wheelchair half-marathon in CSCI was strongly associated with the autonomic dysfunction present in this group.

Serum levels of interleukin-6 (IL-6) are increased in patients with type 2 diabetes (T2D). IL-6 exerts its pleiotropic effects via the IL-6 α-receptor (IL-6R), which exists in membrane-bound and soluble (sIL-6R) forms and activates cells via the β-receptor glycoprotein 130 (gp130). The nonsynonymous single-nucleotide polymorphism (SNP) rs2228145 (Asp358Ala) within the IL6R locus is associated with T2D. The aim of this study was to determine whether sIL-6R in combination with soluble gp130 (sgp130) is able to form an IL-6-neutralizing buffer in healthy subjects and whether this is disturbed in T2D. We found that sIL-6R-sgp130 indeed forms an IL-6-neutralizing buffer in the serum of healthy humans, whose capacity is controlled by the SNP of the IL-6R. Circulating sIL-6R-sgp130 levels were lower in T2D subjects ( P < 0.001), whereas IL-6 was high and inversely correlated with sIL-6R ( r  = -0.57, P < 0.001), indicating a severe disturbance of the buffer. This phenomenon is also observed in sex- and age-matched patients with both T2D and atherosclerosis but not in patients with atherosclerosis alone. In conclusion, sIL-6R and sgp130 serum levels were significantly lower in T2D patients compared with healthy subjects or atherosclerosis patients, although IL-6 levels were high. These data suggest that disturbance of the protective buffer may be closely associated with T2D pathophysiology.

Background: Dysregulated inflammation leads to morbidity and mortality in neonates. Neutrophil-mediated inflammation can cause inflammatory tissue damage. The mammalian target of rapamycin (mTOR) pathway governs IL-6Rα protein expression in human neutrophils. Shed IL-6Rα then participates in trans-signaling of IL-6/IL-6Rα to cells not otherwise sensitive to IL-6. Signaling to endothelial cells triggers efferocytosis where macrophages limit persistent inflammation by phagocytizing neutrophils. We hypothesized that preterm neonatal PMNs fail to synthesize IL-6Rα due to alterations in mTOR signaling., Methods: We studied IL-6Rα expression, PAF receptor expression, and mTOR signaling in plasma and PAF-stimulated PMNs isolated from newborn infants and healthy adults using ELISA, real-time RT-PCR, western blotting, flow cytometry, and immunocytochemistry with phospho-specific antibodies., Results: Compared to healthy adults, plasma from neonates contains significantly less soluble IL-6Rα. IL-6Rα mRNA expression in PAF-stimulated PMNs does not differ between neonates and adults, but IL-6Rα protein expression is decreased in preterm neonatal PMNs. Rapamycin, an mTOR inhibitor, blocks IL-6Rα protein expression. mTOR signaling following PAF stimulation is decreased in preterm neonatal PMNs., Conclusions: Preterm neonatal PMNs exhibit decreased mTOR pathway signaling leading to decreased IL-6Rα synthesis. Decreased synthesis of IL-6Rα by neonatal PMNs may result in decreased IL-6/IL-6Rα trans-signaling with prolonged inflammatory response and increased morbidity.

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 [β 5.4 (95% CI 3.3-7.5); p < 0.001, β - 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 [β - 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.

Background: Hyperglycemia with high hemoglobin A1c (HbA1c) levels is associated with significant health risks. However, the relationship between HbA1c levels and the physical functioning status in later life remains uncertain and so is the possible underlying mechanism., Methods: We conducted a prospective study of 2,565 initially well-functioning community-dwelling older adult aged 55 years and older from the Healthy Aging Longitudinal Study in Taiwan. Each participant received baseline measurements of blood HbA1c and inflammatory markers levels and repeated assessments of physical functioning over a mean follow-up period of 5.3 years. We used generalized linear mixed-effects regression to estimate the adjusted changes in the odds ratio for self-reported physical functioning impairment and Short Physical Performance Battery (SPPB) score according to baseline HbA1c levels (categorized into 0.5% increments from <5.5% to ≥7.0%)., Results: HbA1c levels showed a U-shaped relationship with changes in the odds ratio for physical functioning impairment and SPPB score (p for quadratic term < .001). Compared with participants with an HbA1c of 5.5% to <6.0%, those with an HbA1c of <5.5% or ≥7.0% had a higher annual increase in the odds ratio for physical functioning impairment (odds ratio [95% confidence interval] per year, 1.25 [1.04-1.50] and 1.21 [1.04-1.41]) and a higher annualized decrease in SPPB score (coefficient [95% confidence interval], -0.05 [-0.10 to 0.00] and -0.04 [-0.08 to 0.00]). These relationships were nonlinear only in participants with high soluble interleukin-6 receptor levels (>48,124 pg/mL; p for interaction < .05)., Conclusions: High and low HbA1c levels at baseline are associated with faster physical functioning decline, particularly among individuals with elevated circulating soluble interleukin-6 receptor, a sign of enhanced interleukin-6 trans-signaling., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Signaling of the pleiotropic cytokine Interleukin-6 (IL-6) via its soluble IL-6R (sIL-6R) has been termed trans-signaling and is thought to be responsible for the pro-inflammatory properties of IL-6. The sIL-6R can be generated by alternative mRNA splicing or proteolytic cleavage of the membrane-bound IL-6R. However, which stimuli induce sIL-6R release and which endogenous signaling pathways are required for this process is poorly understood. Here, we show that activation of Toll-like receptor 2 (TLR2) on primary human peripheral blood mononuclear cells (PBMCs) and on the monocytic cell line THP-1 induces expression and secretion of IL-6 and the generation of sIL-6R. We show by flow cytometry that monocytes are a PBMC subset that expresses TLR2 in conjunction with the IL-6R and are the major cellular source for both IL-6 and sIL-6R. Mechanistically, we find that the metalloproteases ADAM10 and ADAM17 are responsible for cleavage of the IL-6R and therefore sIL-6R generation. Finally, we identify the Extracellular-signal Regulated Kinase (ERK) cascade as a critical pathway that differentially regulates both IL-6 and sIL-6R generation in monocytes.

Aims: The pro-inflammatory response to interleukin 6 (IL6) trans-signalling in atherosclerosis is driven by the IL6 and soluble IL6 receptor (sIL6R) binary complex. The binary IL6:sIL6R complex is inactivated by sgp130 through the formation of the ternary IL6:sIL6R:sgp130 complex. The aim of this study was to investigate if IL6 trans-signalling, estimated by a ratio between the binary and ternary complexes, associates with the risk of future cardiovascular events (CVE) in a Swedish cohort of 60-year-old men and women (n = 4232)., Methods and Results: Binary and ternary complex levels expressed in nanomol/Litre were derived from serum concentrations of IL6, sIL6R, and sgp130. Cox regression models were used to assess the risk of CVE (myocardial infarction, angina pectoris, and ischaemic stroke, n = 525), expressed as hazard ratio (HR) with 95% confidence interval (CI), associated with increasing circulating levels of the three molecules and with the binary/ternary complex ratio. Estimates were adjusted for the common cardiovascular (CV) risk factors. To assess the level of IL6-trans-signalling, we estimated the binary/ternary complex ratio and then analysed the association with CVE risk. A ratio higher than the median, representing a relative excess of the active binary complex was associated with increased CVE risk (adjusted HR 1.44, 95% CI 1.21-1.72)., Conclusion: The ratio between the functional moieties of IL6 trans-signalling, IL6:sIL6R, and IL6:sIL6R:sgp130, was associated with CVE risk indicating that it could be a promising marker of CV risk and possibly be used in selecting patients for anti-inflammatory therapy.

Introduction: Clear cell renal cell carcinoma (ccRCC) is the most common type among renal cell carcinomas, and anti-angiogenic treatment is currently first line therapy in metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have major influence on patient's quality of life. The need for predictive biomarkers to select those patients most likely to respond to receptor tyrosine kinase inhibitors (rTKI) upfront is urgent. We investigated the predictive value of plasma interleukin-6 (pIL6), interleukin-6 receptor α (pIL6Rα) and interleukin 6 signal transducer (pIL6ST) in mccRCC patients treated with sunitinib., Material and Methods: Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Full blood samples were collected at baseline before start of sunitinib and after every second cycle of treatment during the study time. pIL6, pIL6R and pIL6ST at baseline and week 12 samples were analysed by ELISA. The predictive potential of the candidate markers was assessed by correlation with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed., Results: Low pIL6 at baseline was significantly associated with improved response to sunitinib (Fisher's exact test, p < 0.01). Furthermore, low pIL6 at baseline was significantly associated with improved PFS (log rank, p = 0.04). In addition, patients with a decrease in concentration of pIL6R between baseline and week 12 showed significantly improved PFS (log rank, p = 0.04) and patients with high pIL6ST at baseline showed significantly improved OS (log rank, p = 0.03)., Conclusion: Low pIL6 at baseline in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker., (Copyright © 2019. Published by Elsevier Ltd.)

The purpose of the present study was to identify a biomarker that can predict the response to preoperative chemoradiotherapy (PCRT) in esophageal cancer patients. Twenty-five serum samples collected from patents with esophageal cancer before PCRT (responder = 13, non-responder = 12) were analyzed by quantitative proteomics, and 248 proteins were identified. Among them, the serum levels of leucine-rich alpha-2-glycoprotein 1 (LRG1) were significantly different (p < 0.01) and well discriminated (area under the curve (AUC) of the receiver operating characteristic (ROC) curve >0.8) between responder and non-responder groups. The combination of LRG1 with C-reactive protein (CRP) and soluble interleukin-6 receptor (sIL-6R), which were previously reported as biomarkers predicting PCRT response, further improved the predictive performance, providing an AUC of greater than 0.9. The present results suggest that LRG1 and its combination with CRP and sIL-6R are promising biomarker candidates to predict response to PCRT in esophageal cancer patients.

Background: The clinical features and laboratory parameters of patients with Kawasaki disease (KD) and systemic juvenile idiopathic arthritis (sJIA) occasionally overlap. Therefore, serum levels of cytokine and ferritin are used as markers to distinguish between KD and sJIA. KD patients have a high level of interleukin (IL)-6, low level of IL-18, and no elevation of the level of serum ferritin. Conversely, sJIA patients have a low level of IL-6 and high levels of IL-18 and ferritin in the serum. However, to the best of our knowledge, no case report of KD with a low serum level of IL-6 and extremely high levels of IL-18 and ferritin is found., Case Presentation: A 6-year-old boy presented with a history of fever for 9 days and a rash that appeared 7 days from the onset. He was diagnosed with incomplete KD because of fever, skin rash, oral cavity erythematous changes, and erythema and edema of the hands with laboratory findings of serum albumin level < 3.0 g/dL, elevated alanine aminotransferase level and leukocyturia. Intravenous immunoglobulin and prednisolone and oral aspirin were introduced on the 10th day. Fever subsided 1 day after initiating the treatment, but arthritis of both knees appeared in addition to hepatosplenomegaly. We suspected sJIA, as the serum level of ferritin was 19,740 ng/mL, IL-6 was < 3 pg/mL, and IL-18 was 132,000 pg/mL. Skin desquamation of the fingertips was observed 18 days from the onset; thus, he was finally diagnosed with incomplete KD with arthritis. At 32 days from the onset, we stopped the prednisolone therapy and no symptoms of relapse were observed afterwards. In the follow-up at 16 months from the onset, he had neither signs of active joint or skin involvement, nor cardiac involvement., Conclusions: Although patients with sJIA generally have high serum levels of IL-18 and ferritin, this was a case of incomplete KD with extremely high serum levels of IL-18 and ferritin. Serum cytokine and ferritin are often used for the differential diagnosis of KD and sJIA. We need to recognize the existence of KD with high serum levels of IL-18 and ferritin.

Background: Viral pneumonia is the main type of community-acquired pneumonia (CAP) in children. YKL-40, a chitinase-like protein, is regarded as a biomarker of the degree of inflammation., Methods: Children who were diagnosed with CAP, including viral pneumonia, bacterial pneumonia, and dual infection, were included in the cohort study. The pathogenic diagnosis depended on PCR and immunoassay test. YKL-40 levels were examined twice by enzyme-linked immunoassay (ELISA)., Results: Serum YKL-40 levels were higher in patients with pneumonia than in healthy controls. The admission levels of YKL-40 in serum and Bronchoalveolar lavage (BALFs) indicated a positive correlation with the serum levels of C-reactive protein and other inflammatory cytokines (IL-6 and TNF-α). The disease severity have no correlation with the admission serum levels of YKL-40. Meanwhile, reductions in YKL-40 levels from initial admission levels to day 5 post-admission were correlated with disease severity. The multiple logistic analysis indicated the decreased extent of serum YKL-40 level as an independent prognostic predictor of severe cases in patients with viral pneumonia., Conclusions: Reductions in serum YKL-40 levels on day 5 after receiving therapy is a possible prognostic biomarker for children with viral pneumonia.

Aim: To evaluate the effect of interleukin-6 inhibition with tocilizumab on the cytokine network in patients with acute non-ST-elevation myocardial infarction (NSTEMI)., Methods: 117 patients with acute NSTEMI were randomised to an intravenous infusion of 280 mg tocilizumab or placebo prior to coronary angiography. Blood samples were obtained at baseline, at 6 consecutive points in time during hospitalisation, and at follow-up after 3 and 6 months. Cytokines (n = 27) were analysed with a multiplex cytokine assay., Results: Using a mixed between-within subjects analysis of variance, we observed a significant (p < 0.001) between-group difference in changes for interferon gamma-inducible protein (IP-10) and macrophage inflammatory protein-1β (MIP-1β), due to significant increases in the tocilizumab group during hospitalisation (i.e., IP-10 median change from baseline during hospitalisation (m Δ ), placebo: 3 (-60, 68) pg/ml vs tocilizumab: 209 (69, 335) pg/ml; MIP-1β m Δ , placebo: 5 (-2, 12) pg/ml vs tocilizumab: 39 (24, 63) pg/ml). MIP-1β was inversely correlated to troponin T (r = -0.28, p < 0.05) and neutrophils (r = -0.32, p < 0.05) in the tocilizumab group. In contrast, tocilizumab had only modest or no effects on the other examined cytokines., Conclusions: Tocilizumab led to a selective and substantial increase in IP-10 and MIP-1β during the acute phase of NSTEMI, with no or only minor effects on the other measured cytokines. ClinicalTrials.gov, NCT01491074., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aim of this study was to measure the impact, at 24 h post-exercise, of a single exercise bout on plasma inflammatory markers such as calprotectin, IL-6, sIL-6 R, sgp130 and the hypothalamic-pituitary-adrenal (HPA) axis in children with juvenile idiopathic arthritis (JIA).Twelve children with JIA attended the laboratory on three consecutive days (control day, exercise day and 24 h post-exercise), including a 20-min exercise bout on a cycle-ergometer at 70% of max. HR at 8:30 a.m. on day 2. Plasma concentrations of calprotectin, IL-6, sIL-6 R, sgp130, cortisol, ACTH and DHEA were measured on venous blood samples taken every day.at rest and at 8:30, 8:50, 9:30, 10:30 a.m. and 12:00, 3:00, 5:30 p.m.A single exercise bout increased plasma calprotectin 1.7-fold (p<0.001) but did not increase IL-6 and soluble IL-6 receptors in short-term post-exercise recovery. However, at 24 h post-exercise, calprotectin, IL-6 and its receptors had decreased compared to control-day levels. There was a transient 2-fold increase in post-exercise self-evaluated pain (p=0.03) that disappeared in the evening without repercussions the following day.Physical activity in children with JIA results in a slight transient systemic inflammation but seems to be followed by counter-regulation at 24 h post-exercise with a decrease in proinflammatory markers., Competing Interests: None conflict of interests to declare., (© Georg Thieme Verlag KG Stuttgart · New York.)

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.

Objective: To evaluate the treatment effects of the IL-6R antibody tocilizumab and cyclophosphamide (CTX) in patients with Takayasu arteritis (TA) and explore the mechanism by analyzing their effects on various cytokines., Methods and Materials: This study included 9 TA patients treated with tocilizumab, 15 TA patients treated with CTX and 24 healthy controls. Treatment effects were evaluated based on: (1) Kerr score and Indian Takayasu Clinical Activity Score (ITAS2010), (2) improvement of previous lesions and occurrence of new vascular lesions on magnetic resonance angiography (MRA), (3) changes in various cytokine levels, (4) glucocorticoid sparing, and (5) adverse effects. ELISA was used to analyze the cytokine levels., Results: Before treatment, all the patients had active disease accompanied with elevated C-reactive protein (CRP), serum amyloid A (SAA), interleukin (IL)-6 and pentraxin-3 (PTX3). Moreover, an imbalance in the MMP-TIMP system was also observed in these patients. Among them, IL-6 and MMP-9 levels were significantly associated with vascular enhancement scores and stenosis scores, respectively. At 6months after treatment, improved clinical manifestations and glucocorticoids sparing were observed in both groups without any severe side effects. Although no significant improvement occurred in the vascular stenosis, thickness and enhancement scores in both groups, a more degree of decrease of ESR, CRP level, significantly decreased MMP-9 level and increased MMP-2 level were found in the tocilizumab group than in the CTX group., Conclusions: The IL-6R antibody may be more effective in mitigating vascular inflammation and remodeling than CTX via inhibition of IL-6 and MMP-9., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The interleukin (IL)-6 biological system plays a key role in the pathogenesis of Paget disease (PD) of bone and pathological bone pain. Bone pain, particularly in the lower back region, is the most frequent symptom in patients with PD. This case-control study aimed to evaluate the relationship between the IL-6 system and low back pain (LBP) in patients with PD. We evaluated 85 patients with PD, with the disease localized in the lumbar spine, pelvis, and/or sacrum, and classified them based on the presence or absence of LBP, before and after aminobisphosphonate treatment. We also examined 32 healthy controls without LBP. Before treatment, IL-6 levels in patients with PD were higher than those in the controls, without difference between patients with or without LBP. Patients with PD with LBP (35/85) showed higher IL-6-soluble receptor (sIL-6R) and lower soluble glycoprotein (sgp) 130 levels compared with both patients with PD without LBP and controls (sIL-6R: 46.9 ± 7.4 vs 35.4 ± 8.6 vs 29.9 ± 4.2 ng/mL; sgp130: 307.2 ± 35.4 vs 341.4 ± 41.4 vs 417.1 ± 58.5 ng/mL, respectively). Paget disease remission, 6 months after treatment, is associated with LBP improvement. This phenomenon is associated with reduced sIL-6R levels and increased sgp130 levels in patients with PD with LBP at the baseline. Considering the biological properties of IL-6, sIL-6R, and sgp130, the results of the study suggest that the perception of LBP in patients with PD could be linked to an enhanced transmission of IL-6 signal in the specialized neural system activated by nociceptors.