Systemic Interleukin-6 Levels Research Articles

Interleukin-6/Glycoprotein130 Signaling Inhibition Ameliorates Renal Mitochondrial Dysfunction And Associated Renal Injury In Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and polycystic ovaries. Renal injury, increased central adiposity, and chronic low-grade systemic inflammation are common characteristics of PCOS. Renal inflammation can induce mitochondrial dysfunction, which plays a pivotal role in renal pathophysiology and chronic kidney disease progression. Interleukin-6 (IL-6) is a key inflammatory cytokine that is involved in renal injury progression by activating its soluble receptor (sIL-6R) and a membrane-bound glycoprotein130 (gp130). Serum IL-6 levels are elevated in women with PCOS; however, its role in inducing renal mitochondrial dysfunction and consequently PCOS-mediated renal injury is unknown. Therefore, we aimed to test the hypothesis that hyperandrogenemia increases systemic and renal IL-6 levels, leading to the activation of IL-6/gp130 signaling, which in turn triggers intrarenal mitochondrial dysfunction and renal injury in a well-characterized mouse model of PCOS. Methods: Three-week-old peripubertal female mice were implanted with Silastic tubes filled with the non-aromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle for 12 weeks. Eight weeks post-Silastic tubes implantation, the animals were treated with the IL-6/gp130 signaling inhibitor SC144 (10 mg/kg, SC, 3x/week) or its vehicle for 4 weeks. Body weight (gravimetry), fat mass (EchoMRI), kidney weight (gravimetry), serum IL-6 (Bioplex), glomerular filtration rate (GFR, transcutaneous fluorescence), as well as the renal injury markers urinary albumin to creatinine ratio (UACR, clinical chemistry analyzer), and NGAL (ELISA) were assessed. Renal gp130 protein and IL-6 mRNA expression were quantified by Western blot and RT-qPCR, respectively. The mitochondrial markers cytochrome C, succinate dehydrogenase A (SDHA), the mitochondrial stress protein HSP60, and voltage-dependent anion channel (VDAC) were assessed in the renal tissue by Western blot. H&E stained renal sections were used for histopathological analysis. Freshly isolated kidney mitochondria were used to measure mitochondrial reactive oxygen species (mtROS) by Amplex Red assay. Moreover, mitochondrial complex I and complex II-driven respiration along with complex IV activity were assessed using Oroboros Fluorespirometer. Results: DHT significantly (p<0.05) increased body weight (26.2±0.9 vs. 22.23±0.4 g), fat mass (3.2±0.4 vs. 1.9±0.4 g), kidney weight (365.6 ± 13.1 vs. 257.1 ± 3.7 mg), UACR (1,227±420 vs. 404±169 μg albumin/mg creatinine), urinary NGAL (2-fold), and serum IL-6 levels (2.2-fold). Additionally, DHT increased the expression of renal gp130 and IL-6 (1.5-fold) and decreased GFR (1067.2 ± 59.9 vs. 1335.6 ± 60.3 uL/min/100g body weight). Moreover, cytochrome c levels in PCOS mice were significantly lower (32%), while HSP60 levels were higher (4-fold). The latter changes were associated with higher mtROS generation (2-fold), as well as lower complexes I, II, III, and IV respiration (43-71%). PCOS mice also showed a worsen renal histological structure with congested glomeruli, exfoliation of luminal epithelial lining, and interstitial hemorrhage. SC144 therapy had no effect on kidney weight or GFR; however, it abolished DHT-induced increases in body weight and fat mass. Excitingly, SC144 treatment normalized the levels of UACR, and decreased both glomerular and tubular injury in PCOS mice. It also decreased renal HSP60 levels and mtROS generation and increased complex IV derived respiration. Conclusion and significance: Our findings suggest that IL-6/gp130 activation plays a significant role in renal outcomes in PCOS. Targeting IL-6 signaling could be a novel therapeutic approach to ameliorate renal injury in PCOS women. Supported by NIH grants NIGMS P20GM121334 to KSE, LLYC, and DGR; NIH-NIGMS P30GM149404 to SR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Administration of adiponectin receptor agonist AdipoRon relieves cancer cachexia by mitigating inflammation in tumour-bearing mice.

Cancer cachexia is a life-threatening, inflammation-driven wasting syndrome that remains untreatable. Adiponectin, the most abundant adipokine, plays an important role in several metabolic processes as well as in inflammation modulation. Our aim was to test whether administration of AdipoRon (AR), a synthetic agonist of the adiponectin receptors, prevents the development of cancer cachexia and its related muscle atrophy. The effect of AR on cancer cachexia was investigated in two distinct murine models of colorectal cancer. First, 7-week-old CD2F1 male mice were subcutaneously injected with colon-26 carcinoma cells (C26) or vehicle (CT). Six days after injection, mice were treated for 5days with AdipoRon (50mg/kg/day; C26+AR) or the corresponding vehicle (CT and C26). Additionally, a genetic model, the ApcMin/+ mouse, that develops spontaneously numerous intestinal polyps, was used. Eight-week-old male ApcMin/+ mice were treated with AdipoRon (50mg/kg/day; Apc+AR) or the corresponding vehicle (Apc) over a period of 12weeks, with C57BL/6J wild-type mice used as controls. In both models, several parameters were assessed in vivo: body weight, grip strength and serum parameters, as well as ex vivo: molecular changes in muscle, fat and liver. The protective effect of AR on cachexia development was observed in both cachectic C26 and ApcMin/+ mice. In these mice, AR administration led to a significant alleviation of body weight loss and muscle wasting, together with rescued muscle strength (P<0.05 for all). In both models, AR had a strong anti-inflammatory effect, reflected by lower systemic interleukin-6 levels (-55% vs. C26, P<0.001 and -80% vs. Apc mice, P<0.05), reduced muscular inflammation as indicated by lower levels of Socs3, phospho-STAT3 and Serpina3n, an acute phase reactant (P<0.05 for all). In addition, AR blunted circulating levels of corticosterone (-46% vs. C26 mice, P<0.001 and -60% vs. Apc mice, P<0.05), the predominant murine glucocorticoid known to induce muscle atrophy. Accordingly, key glucocorticoid-responsive factors implicated in atrophy programmes were-or tended to be-significantly blunted in skeletal muscle by AR. Finally, AR protected against lipid metabolism alterations observed in ApcMin/+ mice, as it mitigated the increase in circulating triglyceride levels (-38%, P<0.05) by attenuating hepatic triglyceride synthesis and fatty acid uptake by the liver. Altogether, these results show that AdipoRon rescued the cachectic phenotype by alleviating body weight loss and muscle atrophy, along with restraining inflammation and hypercorticism in preclinical murine models. Therefore, AdipoRon could represent an innovative therapeutic strategy to counteract cancer cachexia.

Estimating the association between systemic Interleukin-6 and mortality in the dialysis population. Re-analysis of the global fluid study, systematic review and meta-analysis

BackgroundSystemic inflammation, measured as circulating Interleukin-6 (IL-6) levels, is associated with cardiovascular and all-cause mortality in chronic kidney disease. However, this has not been convincingly demonstrated in a systematic review or a meta-analysis in the dialysis population. We provide such evidence, including a re-analysis of the GLOBAL Fluid Study.MethodsMortality in the GLOBAL fluid study was re-analysed using Cox proportional hazards regression with IL-6 levels as a covariate using a continuous non-logarithmic scale. Literature searches of the association of IL-6 levels with mortality were conducted on MEDLINE, EMBASE, PyschINFO and CENTRAL. All studies were assessed for risk of bias using the QUIPS tool. To calculate a pooled effect size, studies were grouped by use of IL-6 scale and included in the meta-analysis if IL-6 was analysed as a continuous linear covariate, either per unit or per 10 pg/ml, in both unadjusted or adjusted for other patient characteristics (e.g. age, comorbidity) models. Funnel plot was used to identify potential publication bias.ResultsOf 1886 citations identified from the electronic search, 60 were included in the qualitative analyses, and 12 had sufficient information to proceed to meta-analysis after full paper screening. Random effects meta-analysis of 11 articles yielded a pooled hazard ratio (HR) per pg/ml of 1.03, (95% CI 1.01, 1.03), {I}^{2}= 81%. When the analysis was confined to seven articles reporting a non-adjusted HR the result was similar: 1.03, per pg/ml (95% CI: 1.03, 1.06), {I}^{2}=92%. Most of the heterogeneity could be attributed to three of the included studies. Publication bias could not be determined due to the limited number of studies.ConclusionThis systematic review confirms the adverse association between systemic IL-6 levels and survival in people treated with dialysis. The heterogeneity that we observed may reflect differences in study case mix.Systematic Review RegistrationPROSPERO - CRD42020214198.

Systemic and local vascular inflammation and arterial reactive oxygen species generation in patients with advanced cardiovascular diseases.

Systemic inflammation may cause endothelial activation, mediate local inflammation, and accelerate progression of atherosclerosis. We examined whether the levels of circulating inflammatory cytokines reflect local vascular inflammation and oxidative stress in two types of human arteries. Human internal mammary artery (IMA) was obtained in 69 patients undergoing coronary artery bypass graft (CABG) surgery and left anterior descending (LAD) artery was obtained in 17 patients undergoing heart transplantation (HTx). Plasma levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were measured using ELISA, high-sensitivity C-reactive protein (hs-CRP) was measured using Luminex, and mRNA expression of proinflammatory cytokines in the vascular tissues was assessed. Furthermore, formation of superoxide anion was measured in segments of IMA using 5 uM lucigenin-dependent chemiluminescence. Vascular reactivity was measured using tissue organ bath system. TNF-α, IL-6 and IL-1β mRNAs were expressed in all studied IMA and LAD segments. Plasma levels of inflammatory cytokines did not correlate with vascular cytokine mRNA expression neither in IMA nor in LAD. Plasma TNF-α and IL-6 correlated with hs-CRP level in CABG group. Hs-CRP also correlated with TNF-α in HTx group. Neither vascular TNF-α, IL-6 and IL-1β mRNA expression, nor systemic levels of either TNF-α, IL-6 and IL-1β were correlated with superoxide generation in IMAs. Interestingly, circulating IL-1β negatively correlated with maximal relaxation of the internal mammary artery (r = -0.37, p = 0.004). At the same time the mRNA expression of studied inflammatory cytokines were positively associated with each other in both IMA and LAD. The positive correlations were observed between circulating levels of IL-6 and TNF-α in CABG cohort and IL-6 and IL-1β in HTx cohort. This study shows that peripheral inflammatory cytokine measurements may not reflect local vascular inflammation or oxidative stress in patients with advanced cardiovascular disease (CVD). Circulating pro-inflammatory cytokines generally correlated positively with each other, similarly their mRNA correlated in the arterial wall, however, these levels were not correlated between the studied compartments.

Dynamics in Circulating Proinflammatory Biomarkers for Prognostic Assessment of Patients With Advanced HCC – A Substudy From the SORAMIC Trial

IntroductionPrediction of response to treatment in patients with advanced hepatocellular carcinoma (HCC) may assist in the selection of personalized management.ObjectiveThis exploratory analysis of the palliative arm of the SORAMIC trial (ClinicalTrials.gov NCT01126645) evaluated the prognostic potential of basal and dynamic changes in systemic levels of interleukin 6 (IL-6), interleukin 8 (IL-8), systemic vascular endothelial growth factor (VEGF), and lipopolysaccharide (LPS).MethodsWe evaluated the correlations between overall survival (OS) and concentrations of IL-6, IL-8, VEGF, and LPS at follow-up approximately 7-9 weeks after treatment initialization (FU) compared to baseline (BL) in 90 patients treated either with 90Yttrium (90Y) microspheres combined with sorafenib (n = 44) or with sorafenib (n = 46) alone.ResultsChanges in IL-6 concentration during treatment showed correlations with the outcome. An increase in IL-6 concentration of less than 16.8 pg/mL over baseline readings was associated with better survival [median OS 16.3 months compared with 8.9 months (p = 0.0354)]. Correlations with survival were not observed for VEGF or LPS concentrations at baseline, at FU, or changes between these time points.ConclusionsChanges in IL 6 serum levels at 7-9 weeks after treatment initialization but not in IL 8, VEGF, or LPS add important information on the outcome of advanced HCC patients treated palliatively within the SORAMIC trial.

IL‐6 Signaling is Required for LPS‐induced Barrier Function Loss

Interleukin‐6 (IL‐6) is a major mediator of the cytokine storm in response to severe systemic inflammation and sepsis. This cytokine promotes the activation of the transcription factor STAT3 via Janus kinases (JAK)‐dependent phosphorylation on tyrosine 705. Prior work in our lab demonstrated that overactivation of this pathway within the endothelium via an endothelial‐specific deletion of the negative regulator SOCS3 (SOCS3iEKO) leads to kidney failure and acute mortality after a single lipopolysaccharides (LPS) challenge that was non‐lethal in wild‐type mice. This mortality was associated with increased systemic IL‐6 levels and vascular leak in lungs and brain of SOCS3iEKO mice. Furthermore, translating ribosome affinity purification studies showed that in response to LPS, the kidney and brain endothelia expressed high levels of IL‐6. These findings suggested that IL‐6 signaling within the endothelium might be required to promote vascular leak. To sought to test this hypothesis in vitro. We found that LPS promoted a mild increase in monolayer permeability in HUVEC that was abrogated by pretreatment with the JAK inhibitor ruxolitinib. This loss of barrier function by LPS was associated with an increase in IL‐6 expression and a modest increase in STAT3 phosphorylation. Endothelial cells express very low levels of the gp80 subunit of the IL‐6 receptor. Thus, to test whether an IL‐6 autocrine loop induced barrier function loss, we treated cells with LPS in the presence or absence of a soluble form of gp80 (herein, LPS+R). LPS+R‐treated cells showed increased STAT3 phosphorylation and severe barrier function loss. A similar increase in STAT3 phosphorylation and monolayer permeability was observed when gp80 was added to TNF‐treated cells. In contrast, addition of gp80 to LPS‐ or TNF‐treated cells did not alter the levels of p65RelA or p38 phosphorylation. Pretreatment of LPS+R‐treated cells with the p38 inhibitor SB203580 showed that activation of p38 signaling was not required for STAT3 phosphorylation or barrier function loss. In summary, our data strongly suggest that the endothelium responds to strong inflammatory challenges with an increase in IL‐6 expression that may act in an autocrine fashion to promote strong barrier function loss, potentially explaining the systemic vascular leak observed in critically ill patients with high circulating IL‐6 levels.

The Role of IL-6 in Inflammatory Reaction during Coronavirus-19 Infection: A Review

Interleukin 6 (IL-6) is an interleukin that works as a pro-inflammatory cytokine and as an anti-inflammatory myokine. The production of IL-6 in humans is under genetic control. IL-6 is a pleiotropic cytokine created in response to tissue injury and infections. IL-6 is one of the basic cytokines after stimulated macrophages. Hence, control of systemic IL-6 levels in SARS-CoV-2 infected patients may be a consideration for COVID-19 disease. This review will focus on the role of IL-6 in diagnosis and follow up of infection in addition to being the target for treatment.

“Reconnoitering the Association of Interleukin-6 with Chronic Periodontitis and Covid-19: An Observational Study

Aim: The aim of the present study was to investigate comparatively the systemic levels of interleukin-6 in COVID-19 positive patients with/without chronic periodontitis and recovered COVID-19 patient with/without chronic periodontitis respectively. Methods: Total 200 consecutive confirmed cases were included and categorized equally into four groups- Group1A &amp; Group 1B (COVID-19 positive), Group 2A &amp; Group 2B (COVID-19 recovered),based on periodontal status along with Interleukin-6 levels. Peripheral blood samples were taken and Serum Interleukin-6 concentrations were tested using a highly sensitive (Chemiluminescence immunoassay) CLIA method on admission during hospital stay. Results: There were 50 subjects taken in all study groups. The mean age was 40.80, 38.02, 41.06, 38.98 in Group (1A,1B,2A&amp;2B) respectively and the difference in mean age group was not significant (P&gt;0.05). The mean interleukin-6 level was 26.0752, 1.5306, 4.1290, 0.7514 pg/ml in Group1A, 1B, 2A, 2B respectively and the difference was statistically significant (P-0.0001*). The mean difference in inter-group comparison was seen significant (P&lt;0.05) among group1A vs(1B,2A,2B) &amp; non-significant (P&gt;0.05) among group1Bvs(2A,2B) &amp; group2A vs 2B respectively. Conclusion: Chronic periodontitis must be included in diagnostic work-up to stratify SARS- CoV-2 severity.

Extracorporeal Blood Purification in Moderate and Severe COVID-19 Patients: A Prospective Cohort Study

Introduction: Coronavirus disease 2019 (COVID-19) is characterized by hyperinflammation and coagulopathy. Severe cases often develop respiratory distress, requiring mechanical ventilation and with critical cases progressing to acute respiratory distress syndrome. Control of hyperinflammation has been proposed as a possible therapeutic avenue for COVID-19; extracorporeal blood purification (EBP) modalities offer an attractive mean to ameliorate maladaptive inflammation. With this work, we evaluated the longitudinal changes of systemic inflammatory markers in critically ill COVID-19 patients treated with blood purification using AN69ST (oXiris®) haemofilter. Methods: We performed a time-series analysis of 44 consecutive COVID-19 cases treated with the AN69ST (oXiris®) cytokine adsorbing haemofilter (CAH) according to local practice; we visualize longitudinal results of biochemical, inflammatory, blood gas, and vital sign parameters focussing on systemic levels of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin. Results: All patients were treated with ≥1 cycle extracorporeal continuous venovenous haemofiltration (CVVH) with CAH; of these, 30 severe patients received CVVH-CAH within 4–12 h of admission after recognizing a hyper-inflammatory state. Another 14 patients admitted with mild-to-moderate symptoms progressed to severe disease and were placed on EBP during hospitalization. The treatment was associated with a reduction of ferritin, CRP, fibrinogen, several inflammatory markers, and a resolution of numerous cytopenias. The observed mortality across the cohort was 36.3%. Conclusion: EBP with CAH was associated with a decrease in CRP, and control of IL-6 and procalcitonin.

Effects of a 6 Week Low-Dose Combined Resistance and Endurance Training on T Cells and Systemic Inflammation in the Elderly

With increasing age, the immune system undergoes a remodeling process, affecting the shift of T cell subpopulations and the development of chronic low-grade inflammation. Clinically, this is characterized by increased susceptibility to infections or development of several diseases. Since lifestyle factors can play a significant role in reducing the hallmarks of immune aging and inflammation, we investigated the effect of a 6 week low-dose combined resistance and endurance training program. Forty participants (70.3 ± 5.0 years) were randomly assigned to either a training (TG) or control group (CG) and performed a controlled low-threshold and care-oriented 6-week-long combined resistance and endurance training program. Changes in anthropometrics as well as strength capacity were measured. In subgroups of TG and CG, T cells and their subpopulations (CD4+, CD8+, naïve, central, effector memory, T-EMRA) were analyzed by flow cytometry. The changes of various plasma cytokines, chemokines, growth factors and adipokines were analyzed by luminex assays. The exercise program was followed by an increase in strength capacities. Participants of TG showed an increase of the CD4+/CD8+ T cell ratio over time (p < 0.05). Significant decreases in systemic levels of interleukin (IL-) 6, IL-8, IL-10 and vascular endothelial growth factor (VEGF) (p < 0.05) were observed for participants of TG over time. Even short-term and low-threshold training can reduce some of the hallmarks of immune aging in elderly and thus could be beneficial to stimulate immunity. The specific characteristics of the program make it easily accessible to older people, who may benefit in the longer term in terms of their immunocompetence.

Pro‐inflammatory cytokine interleukin‐6‐induced hepcidin, a key mediator of periodontitis‐related anemia of inflammation

To investigate whether anemia of inflammation (AI) occurs in periodontitis patients and to further explore underlying pathogenesis of periodontitis-related AI by an experimental periodontitis model. Previous studies have reported periodontitis patients could show a tendency toward AI. However, the relationship between periodontitis and AI remains unclear, and the related pathological mechanisms have not been identified. Periodontal clinical parameters, inflammatory markers, and anemia-related indicators were compared between 98 aggressive periodontitis (AgP) patients and 103 healthy subjects. An experimental periodontitis model was induced by ligature placement in mice. The changes in mice inflammatory markers, anemia indicators, hepcidin mRNA expression, and serum hepcidin concentrations were measured. Human and mouse liver cells were treated with interleukin-6 (IL-6) for analyzing the changes in hepcidin expression based on mRNA and protein levels. AgP patients exhibited higher white blood cell counts, IL-6, and C-reactive protein. Adjusted linear regression analyses showed correlations between AgP and decreased hemoglobin (HGB) and hematocrit (HCT). The ligature-induced periodontitis caused systemic inflammation and elevated IL-6 levels. Lower red blood cell counts, HGB, and HCT were detected, whereas the levels of hepcidin mRNA expression and serum hepcidin concentrations increased. The treatment of hepatocytes with IL-6 induced both hepcidin mRNA expression and hepcidin secretion. Systemic inflammation induced by periodontitis leads to an increased risk for AI. IL-6-induced hepcidin could play a central mediator role and act as a key pathologic mechanism. Our results demonstrate periodontitis may be considered as an additional inflammatory disease contributing to the development of AI.

Does Interleukin-6 Bridge SARS-CoV-2 With Virus-Associated Cancers?

To date SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), a member of the Coronaviridae family, has infected more than 40 million people worldwide. A second wave of SARS-CoV-2 infection is aggressively surging. The clinical worsening of SARS-CoV-2 infection appears to be strictly associated with comorbidities, which can be used to establish an intrinsic patient network whose molecular profile is pivotal for identifying and successfully treating populations at risk. Herein, we focus on the direct interaction between SARS-CoV-2 and virus-associated cancers, exploring the critical role of interleukin-6 (IL-6) as a mediator of this complex cross talk. IL-6 production is enhanced in diverse viral infections ranging from human papilloma virus (HPV) to hepatitis B virus (HBV), human immunodeficiency virus (HIV), and SARS-CoV-2 infection. High systemic levels of IL-6 are associated with viral persistence and poor clinical outcomes in SARS-CoV-2-infected patients. Blockade of IL-6/IL-6R, using specific molecules, is under investigation in active clinical trials for the treatment of patients with SARS-CoV-2. Although the data are as yet inconclusive, they pave the way for selective targeting of crucial cytokine-activated aberrant signaling in SARS-CoV-2 infection.

Roux-en-Y gastric bypass decreases serum inflammatory markers and cardiovascular risk factors in obese diabetics

BackgroundObesity and type 2 diabetes mellitus are associated with elevated levels of inflammatory markers. This chronic inflammation is known to contribute to increased risk of cardiovascular disease in these populations. Laparoscopic Roux-en-Y gastric bypass is associated with a high rate of diabetes remission. We hypothesize that laparoscopic Roux-en-Y gastric bypass decreases systemic inflammatory markers and cardiovascular disease risk factors in obese diabetics. MethodsThis was a single-institution prospective cohort study of 61 obese patients with type 2 diabetes mellitus. A total of 30 patients underwent laparoscopic Roux-en-Y gastric bypass surgery, and 31 patients underwent standard medical therapy with diabetes support and education. Collected data included preoperative and postoperative inflammatory biomarkers and clinical parameters. ResultsTwelve months after undergoing laparoscopic Roux-en-Y gastric bypass, controlling for sex and age, there was a significant correlation between a change in interleukin-6 and a change in systolic blood pressure (Spearman r = 0.41, P = .03). Similarly, when sex and age were controlled for in the laparoscopic Roux-en-Y gastric bypass group, a statistically significant relationship remained between percent excess weight loss and change in interleukin-6 (P = .001). ConclusionA significant relationship exists between decreased systemic interleukin-6 levels and both excess weight loss and lowered systolic blood pressure after laparoscopic Roux-en-Y gastric bypass in obese patients with diabetes mellitus. These correlations may explain the decreased risk of cardiovascular disease after surgical weight reduction in this patient population.

Impact of epicardial adipose tissue increase after ST elevation Myocardial Infarction (STEMI) on IL-13 and left ventricular remodelling

Abstract Background The role of epicardial adipose tissue (EAT) in myocardial diseases is well established, and several evidence suggest that EAT may negatively affect left ventricular (LV) remodelling through an imbalanced production and secretion of pro and anti-inflammatory cytokines. Of these, the IL-13 it is known to play a positive activity on cardiac remodelling. Nowadays, the crosstalk between EAT and the myocardium is still poorly understood and the effects of myocardial ischemia on morphological and functional properties of EAT are almost unknown. Purpose In the present study we explored whether an increase of EAT thickness after STEMI might be associated with unfavourable LV remodelling at 3 months (T1). We also evaluated the relationship between changes (Δ) of EAT thickness and systemic levels of Interleukin (IL)-13 which is known to play a favourable activity on LV remodelling after STEMI. Methods We enrolled 66 patients with first STEMI, undergoing primary percutaneous angioplasty. At baseline and at 3 months we performed a complete echocardiogram, including EAT maximal thickness assessment, and determined circulating levels of IL-13. Results At 3 months after STEMI, the population was stratified into two groups according to different EAT remodelling after cardiac event: Group 1, patients with an increased EAT thickness (Δ EAT&amp;gt;1; 30 patients) and Group 2, patients with unchanged or decreased EAT thickness (Δ EAT&amp;lt;1). The two groups did not differ for age, gender and atherosclerotic risk factors. Group 1 had a worse LV remodelling at 3 months with higher LV diastolic and systolic volumes, lower LV ejection fraction (p=0.003; p=0.013; p=0.013 respectively) and worse diastolic function (E/e'; p=0.011). Of interest, EAT thickness increase was paralleled by circulating IL-13 reduction (p=0.022). Conclusion Myocardial injury can result in EAT increase which is associated to worse LV remodelling probably through the loss of the protective role of IL-13. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This research has been funded by the University of Naples “Federico II” and “Compagnia di San Paolo e l'Istituto Banco di Napoli” within the competitive grant STAR 2018; Valentina Parisi is the principal investigator

IL-6: Relevance for immunopathology of SARS-CoV-2

COVID-19 mortality is strongly associated with the development of severe pneumonia and acute respiratory distress syndrome with the worst outcome resulting in cytokine release syndrome and multiorgan failure. It is becoming critically important to identify at the early stage of the infection those patients who are prone to develop the most adverse effects. Elevated systemic interleukin-6 levels in patients with COVID-19 are considered as a relevant parameter in predicting most severe course of disease and the need for intensive care. This review discusses the mechanisms by which IL-6 may possibly contribute to disease exacerbation and the potential of therapeutic approaches based on anti-IL-6 biologics.

Systemic levels of interleukin-6 in patients with age-related macular degeneration: a systematic review and meta-analysis.

Age-related macular degeneration (AMD) is the most prevalent cause of irreversible vision loss in industrialized countries. Several studies have investigated systemic interleukin-6 (IL-6) levels of patients with AMD. In this study, we systemically reviewed the literature to provide an overview of the field and used meta-analyses to provide a summary estimate of the standardized mean difference (SMD) of systemic IL-6 between patients with AMD and control individuals. We searched the literature databases PubMed/MEDLINE, Embase, Web of Science and the Cochrane Central on 1 June 2019 for relevant studies on humans. Two authors independently extracted data and evaluated risk of bias. We identified 19 studies for the qualitative review with a total of more than 3586 individuals (1865 controls and 1721 with AMD). We found an overall random-effects SMD in systemic IL-6 levels 0.63 (95% CI: 0.28 to 0.99, p=0.0005) corresponding to a medium effect size. In a subgroup analysis, we found that early AMD was not strongly associated with elevated IL-6 levels (0.12, 95% CI: -0.01 to 0.24, p=0.06), which was in contrast to the significantly elevated IL-6 levels in patients with geographic atrophy (1.21, 95% CI: 0.41 to 2.01, p=0.003) and patients with neovascular AMD (0.99, 95% CI: 0.34 to 1.63, p=0.003). Our results show that the evidence today suggests an increased systemic IL-6 in patients with AMD, but that this may be a phenomenon more closely related to the late subtypes of AMD.

Mast Cell Degranulation Decreases Lipopolysaccharide-Induced Aortic Gene Expression and Systemic Levels of Interleukin-6 In Vivo.

Mast cells play an important role in immunomodulation and in the maintenance of vascular integrity. Interleukin-6 (IL-6) is one of the key biomarkers and therapeutic target in systemic vasculitis. The objective of the current study is to describe the role of mast cells in arterial IL-6 homeostasis. Eight- to ten-week-old male C57BL/6 (wild-type) mice were injected with either (a) saline, (b) compound 48/80 (a systemic mast cell degranulating agent), (c) lipopolysaccharide (LPS), or (d) a combination of C48/80 and LPS. Twenty-four hours after the injections, mice were sacrificed and serum samples and aortic tissues were analyzed for determining inflammatory response and cytokine expression profile. The results revealed that induction of mast cell degranulation significantly lowers serum IL-6 levels and aortic expression of IL-6 in LPS-treated mice. Significantly higher aortic expression of toll-like receptor-2 (TLR-2) and TNF-α was seen in the LPS and LPS+C48/80 groups of mice compared to controls. Aortic expression of TLR-4 was significantly decreased in LPS+C48/80 compared to C48/80 alone. LPS+C48/80-treated mice presented with a 3-fold higher aortic expression of suppressor of cytokine signaling (SOCS-1) compared to saline-injected groups. The inhibition of LPS-induced increase in serum IL-6 levels by mast cell degranulation was not seen in H1R knockout mice which suggests that mast cell-derived histamine acting through H1R may participate in the regulatory process. To examine whether the mast cell-mediated downregulation of LPS-induced IL-6 production is transient or cumulative in nature, wild-type mice were injected serially over a period of 10 days (5 injections) and serum cytokine levels were quantified. We found no significant differences in serum IL-6 levels between any of the groups. While mice injected with C48/80 or LPS had higher IL-10 compared to vehicle-injected mice, there was no difference between C48/80- and LPS+C48/80-injected mice. In conclusion, in an in vivo setting, mast cells appear to partially and transiently regulate systemic IL-6 homeostasis. This effect may be regulated through increased systemic IL-10 and/or aortic overexpression of SOCS-1.

Effects of Exercise Training and IL-6 Receptor Blockade on Gastric Emptying and GLP-1 Secretion in Obese Humans: Secondary Analyses From a Double Blind Randomized Clinical Trial.

BackgroundInterleukin-6 (IL-6) is released from skeletal muscle during exercise and systemic IL-6 levels therefore increase acutely in response to a single bout of exercise. We recently showed that an acute increase in IL-6 delayed gastric emptying rate and improved postprandial glycemia. Here we investigate whether repeated increases in IL-6, induced by exercise training, influence gastric emptying rate and moreover if IL-6 is required for exercise-induced adaptations in glycemic control including secretion of glucagon and glucagon-like peptide-1 (GLP-1).MethodsA total of 52 abdominally obese non-diabetic men and women were randomly assigned into four groups performing 12 weeks of endurance exercise or no exercise with or without IL-6 receptor blockade (tocilizumab). The primary endpoint was change in gastric emptying rate in response to the intervention and other endpoints included changes in glycemic control, glucagon, and GLP-1 secretion.ResultsThere was no change in gastric emptying rate in any of the four groups following the intervention and comparing differences in change between groups also revealed no difference. Postprandial glucose remained unchanged in all groups but the exercise + tocilizumab group, which improved postprandial glucose in response to the intervention. The area under the curve for meal-stimulated glucagon, active and total GLP-1 increased in response to IL-6 receptor blockade, this effect was independent of exercise.ConclusionExercise training and long-term IL-6 receptor blockade did not change gastric emptying rates in obese humans. IL-6 receptor blockade increased glucagon and GLP-1 secretion and implicate IL-6 in the regulation of the human alpha and L cells.

EFFECT OF A 12-WEEK YOGA-BASED LIFESTYLE INTERVENTION ON BLOOD PRESSURE, INSULIN RESISTANCE AND INFLAMMATORY MEDIATORS IN PRE-DIABETIC OVERWEIGHT/OBESE INDIANS

Objective: Background: Obesity is an independent risk factor for type-2-diabetes and other cardio-metabolic conditions, mediated by insulin resistance and disturbed inflammatory adipokines profile. To study the effect of a 12-week Yoga-based lifestyle intervention (YBLI) on blood pressure, insulin resistance, and systemic inflammatory markers in pre-diabetic, overweight/obese Indian adults. Design and method: Methodology: Prospective, single-arm, lifestyle intervention study was conducted in pre-diabetic (n = 55), overweight/ obese (fasting plasma glucose, FPG 100 to 125 mg/dL; body mass index; BMI 23–40 Kg/m2) subjects. The subjects were assigned with pretested YBLI consisting of asanas, pranayama, meditation and relaxation techniques with group support, dietary advice under supervision for approx. 2 hrs each day for 2 weeks followed by the continuation of the same practices at home for next 10 weeks. Outcome measures were weight, waist to hip ratio (WHR), FPG, serum insulin, blood pressure (BP), homeostatic model insulin resistance (HOMA-IR) and plasma levels of tumor necrosis factor (TNF) -alpha, interleukin-6 (IL-6) and leptin, adiponectin measured before and after the intervention. Results: After intervention, subjects (mean age = 38.5 ± 5.5 years, BMI = 30.4 ± 4.1 Kg/m2) had significant reduction in weight, WHR, systolic BP, diastolic BP, and HOMA-IR. There was statistically significant reduction in IL-6 {median (range) 1.1 (0.5, 2.4) vs. 0.8 (0.4,1.5) pg/mL, p = 0.02} and leptin {22.9 (13.9, 45.0) vs. 21.6 (12.0, 42.6) ng/mL, p < 0.01)}; and significant increase in adiponectin {6.0 (4.4, 7.6) vs. 6.5 (4.7, 9.2) ng/mL, p < 0.02)}; while no significant difference was noticed in TNF-alpha levels. Conclusions: Conclusion: Pre-diabetic Indians who underwent 12-week YBLI showed favourable beneficial changes in blood pressure, insulin resistance, and systemic levels of IL-6, leptin and adiponectin, resulting in overall reduction in cardiovascular risk.

Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome Is Associated With Dysregulation of IL-7/IL-7 Receptor Signaling Pathway in T Cells and Monocyte Activation.

Systemic levels of interleukin (IL)-7 at antiretroviral therapy (ART) initiation have previously been shown to be predictive of HIV-linked paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). We therefore explored IL-7/IL-7 receptor (IL-7/IL-7R) signaling pathway dysfunction, with related alterations in immune function, as a mechanism underlying C-IRIS. HIV-infected patients with cryptococcal meningitis who experienced C-IRIS (n = 27) were compared with CD4 T-cell count-matched counterparts without C-IRIS (n = 27), after antifungal therapy and pre-ART initiation. Flow cytometry was used to assess T-cell and monocyte phenotypes and functions. Proportions of IL-7R+ CD4 or CD8 T cells correlated positively with CD4 T-cell counts and proportions of central memory and naive CD4 and CD8 T-cell pre-ART (all r > 0.50 and P < 0.05); however, the former negatively correlated with CD4 T-cell counts fold-increase on ART in non-C-IRIS but not C-IRIS patients. Higher frequencies of activated monocytes (CD14CD86 or CD14+HLA-DR+; P ≤ 0.038) were also observed in C-IRIS compared with non-C-IRIS patients, and those who failed to clear cryptococci from cerebrospinal fluid before ART had higher levels of activated monocytes (CD14+HLA-DR+, P = 0.017) compared with those who cleared. In multivariate regression, CD14+HLA-DR+ monocytes were independently associated with C-IRIS [hazard ratio = 1.055 (1.013-1.098); P = 0.009]. In contrast to non-C-IRIS patients, C-IRIS patients displayed a lack of association between proportions of IL-7R+ T cells and several markers of T-cell homeostasis. They also exhibited higher monocyte activation linked to cerebrospinal fluid cryptococcal culture positivity before ART. These data suggest a role for IL-7/IL-7R signaling pathway dysregulation in the pathogenesis of C-IRIS, possibly linked to monocyte activation and residual pathogen burden before ART.