Including Interleukin-6 Levels Research Articles

Quantification of Plasma Proteins from Idiopathic Multicentric Castleman Disease Flares and Remissions Reveals ‘Chemokine Storm’ and Separates Clinical Subtypes

Introduction: Human Herpesvirus-8(HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a poorly understood disease involving polyclonal lymphoproliferation, constitutional symptoms, and life-threatening multi-organ failure. Some patients experience thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO Syndrome) while others (non-TAFRO) experience thrombocytosis and hypergammaglobulinemia. Though the etiology is unknown, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often including interleukin-6 (IL-6). Anti-IL-6 therapy with siltuximab was approved by the FDA to treat iMCD based on superior efficacy compared to placebo in a randomized trial. However, approximately one-half of iMCD patients do not respond to anti-IL-6 therapy. Few rational treatment options exist for anti-IL-6 non-responders, because alternative driver cytokines and signaling pathways are not known. Furthermore, no positive diagnostic biomarkers exist for iMCD. We systematically characterized proteomic changes that occur in iMCD patients between flare and remission to identify key cytokines, signaling pathways, and cell types that may be involved in pathogenesis.Methods: Using Somalogic's modified aptamer-based proteomics platform, SOMAScan, we quantified 1,129 plasma proteins from six iMCD patients at the University of Arkansas for Medical Sciences during flare and remission. Two cases were confirmed to have TAFRO syndrome, and four cases did not have TAFRO syndrome. Proteomic data for two sets of healthy controls were obtained post-hoc and merged with the iMCD proteomic data along common calibrated proteins. Data analysis was performed using R 3.3.3.Results: Principal component analysis (PCA) revealed a distinction between iMCD samples-in flare and remission-and healthy control samples. Reactome pathway analyses identified cytokine signaling, chemokine signaling, and the complement cascade as the most enriched pathways compared to the background proteins assayed. Chemokines represented the greatest proportion of two-fold up-regulated cytokines in flare compared to interleukins and other cytokines. The chemokine, B Lymphocyte Chemoattractant (BLC)/CXCL13, was the most significantly upregulated cytokine across all patients. IL-6 was surprisingly not among the most upregulated cytokines. Five of six patients had less than two-fold up-regulation and the only patient with greater than two-fold up-regulation did not improve with anti-IL-6 receptor monotherapy. However, three of the other four patients treated with anti-IL-6 or anti-IL-6 receptor monotherapy experienced responses despite small changes in IL-6 levels between flare and remission. We observed a distinct proteomic profile between the TAFRO and non-TAFRO patients according to PCA, correlation analyses, and hierarchical clustering. The two TAFRO patients also both failed to respond to anti-IL-6 monotherapy. A large proportion of proteins significantly up- or down-regulated in non-TAFRO patients were conversely up- or down-regulated in TAFRO patients.Discussion: This study provides the first unbiased quantification of circulating proteins in iMCD patients during flare and remission. PCA of these data suggest that the proteomic profile of iMCD patients differs from that of healthy individuals even during remission. Our results support the field's assertion that iMCD involves a cytokine storm, but increased IL-6 was not uniformly present. The response of three patients to anti-IL-6 treatment suggests that IL-6 plays a critical role in these patients despite subtle changes in IL-6 levels. The increased proportion of up-regulated chemokines relative to other cytokines suggests that iMCD involves a chemokine storm. CXCL13 plays an essential role in honing B cells to germinal centers, which are uniformly dysmorphic in iMCD with either too few (atrophic) or too many B cells (hyperplastic). Lymph node stromal cells are known to produce three of the most up-regulated chemokines (CXCL13, CCL19 and CCL21), suggesting that they may play a role in pathogenesis. The distinct proteomic profiles between TAFRO (both anti-IL-6 non-responders) and non-TAFRO (responders) cases suggest that differing mechanisms may be involved. Larger studies are needed to confirm these findings and investigate chemokines in iMCD pathogenesis. DisclosuresFajgenbaum:Janssen Pharmaceuticals: Research Funding.

Resveratrol ameliorated endothelial injury of thoracic aorta in diabetic mice and Gly-LDL-induced HUVECs through inhibiting TLR4/HIF-1α.

To explore the effects of resveratrol on the levels of inflammatory cytokines and Toll‐like receptor‐4/ hypoxia‐inducible transcription factors‐1α (TLR4/HIF‐1α) signalling pathway in diabetes mellitus. C57BL/6 mice received intraperitoneal injection of streptozocin for constructing diabetic mice models. Human umbilical vein endothelial cells (HUVECs) were treated with 50 µg/mL Gly‐LDL for inducing injury models. 10, 100 and 1000 mmol/L resveratrol were obtained and added into each group. Haematoxylin‐eosin (H&E) staining was used for histological evaluation. CCK8 assay was performed for determination of cell viability, and Transwell assay was implemented for detecting cell migration ability. Cell apoptosis was analysed using flow cytometry. The content of inflammatory factors including interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α), vascular adhesion molecule‐1 (VCAM‐1) and vascular endothelial growth factor (VEGF) were measured by ELISA. GST pull‐down assay was employed for determining interactions between TLR4 and HIF‐1α. The protein expression of TLR4 and HIF‐1α was detected using Western blotting and immunohistochemistry, while relative mRNA expression was measured by RT‐qRCR. Resveratrol could reduce bodyweight and ameliorate endothelial injury of thoracic aorta in diabetic mice. Both in vivo and in vitro results revealed that the level of IL‐6, TNF‐α, VCAM‐1 and VEGF was significantly down‐regulated after being treated with resveratrol. Resveratrol inhibited the increase of MDA and ROS and increased the level of SOD in diabetic mice. Western blotting, IHC and RT‐qPCR results showed that the levels of TLR4 and HIF‐1α were significantly down‐regulated in resveratrol group. Overexpression of TLR4 or HIF‐1α could reverse the effect of resveratrol. GST pull‐down elucidated that there might be a close interaction between TLR4 and HIF‐1α. Resveratrol ameliorated endothelial injury of thoracic aorta in diabetic mice and Gly‐LDL‐induced HUVECs through inhibiting TLR4/HIF‐1α signalling pathway.

Protective Effect of a Formulation Containing Pistacia atlantica Oleo-Gum-Resin and Honey on Experimental Model of Acetic Acid-Induced Colitis in Rats

Background and objectives: Inflammatory bowel disease (IBD) is a recurrent chronic inflammatory disease of the gastrointestinal tract. In Iranian traditional medicine, the oleo-gum-resin of the genus Pistacia is recommended for treatment of various diseases including gastrointestinal disorders. The present study investigated the therapeutic action of a combination of Pistacia atlantica subspecies kurdica oleo-gum-resin and honey in acetic acid-induced colitis in rats. Methods: Pistacia atlantica oleo-gum-resin was mixed with honey. The mixture was suspended in distilled water. Following induction of colitis with 4% acetic acid in all animals, except in sham group,themixture was orally administered for two consecutive days at the concentrations of 100, 200, 400 mg/kg. Other groups included the control, sham and a standard group (dexamethasone). Microscopic and histopathologic examinations were conducted in inflamed colonic tissue. The inflammatory biomarkers of colitis including interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and myeloperoxidase (MPO) and the gene expression level of toll like receptor-4 (TLR-4) were assessed. Results: Pistacia atlantica oleo-gum-resin+ honey induced significant progress in macroscopic and microscopic scores. Colonic levels of MPO, IL-6, and TNF-α significantly declined in rats treated with the mixture; while significant decrease in mucosal gene expression of TLR-4 and significant improvement of colitis were observed. Pistacia atlantica oleo-gum-resin (400 mg/kg) + honey (400 mg/kg)reduced inflammation of the bowel and colonic ulcer severity shown by downregulation of inflammation cytokines, reduction of neutrophil infiltration, and suppression of TLR-4 expression. Conclusion: The combination might be a promising supplement for treatment of inflammatory disorders.

Inhibition of inflammation-induced injury and cell migration by coelonin and militarine in PM2.5-exposed human lung alveolar epithelial A549 cells

Accumulating studies suggest that fine particulate matter (PM2.5) pollutants in the air are easily enter into alveoli and even the bloodstream, resulting in an inflammatory response that not only triggers respiratory disorders but also causes permanent damage to various organs. Recent findings suggest that coelonin and militarine enriched in orchids can inhibit inflammation-induced injury against respiratory diseases. Here, we evaluated the anti-inflammatory properties of coelonin and militarine and examined their underlying molecular mechanisms in A549 cells exposed to PM2.5. PM2.5 induced significant intracellular reactive oxidative stress accumulation at a concentration of 250 μg/ml, as determined using the dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay. Cell viability was assessed via the MTS assay to determine the concentrations of compounds appropriate for use in subsequent experiments. Data from the enzyme-linked immunosorbent assay (ELISA) showed that both coelonin (10 and 20 μg/ml) and militarine (5 and 10 μg/ml) mitigated PM2.5-induced inflammation by reducing the generation of inflammatory factors, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Quantitative real-time PCR (qRT-PCR) analysis revealed a remarkable decrease in IL-6, TNF-α, cyclooxygenase-2 (COX-2) and interleukin-1β (IL-1β) mRNA levels in the coelonin and militarine-pretreated groups. In Western blot analysis, expression of inhibitor of NF-κB (IκBα) protein in the coelonin and militarine pretreatment groups was significantly increased compared with the PM2.5 (only) treatment group (P < 0.05), concomitant with a significant decrease in phospho-IκB kinase β/IκB kinase β (p-IKKβ/IKKβ), phospho-nuclear factor of kappa B p65/nuclear factor of kappa B p65 (p–NF–κBp65/NF-κBp65) and COX-2 proteins (P < 0.05). Both coelonin and militarine inhibited migration and inflammation by suppressing PM2.5-induced IKK phosphorylation, and followed by IκBα protein degradation and NF-κB activation. Our collective data strongly supported the utility of coelonin and militarine as novel sources for development of treatments for PM2.5-induced lung diseases.

The retrospective study of perioperative application of dexamethasone and furosemide for postoperative anti-inflammation in patients undergoing percutaneous nephrolithotomy

ObjectivesTo investigate whether the perioperatively combined application of dexamethasone and furosemide could alleviate the inflammation in patients undergoing percutaneous nephrolithotomy (PCNL).Patients and methods147 patients undergoing PCNL between November 2018 and October 2019 were enrolled in the study. 77 patients accepted a single dose of dexamethasone and furosemide administration (EXP group, n = 77), and 70 patients did not (CON group, n = 70). Demographic and perioperative data, inflammatory markers including interleukin-6 (IL-6) and procalcitonin (PCT), and clinical outcomes were compared between the two groups.ResultsCompared with the CON group, the incidence rate of urosepsis of the EXP group were significantly lower (11.69% vs. 24.29%, p = 0.046). 3 patients developed severe urosepsis in the EXP group, while 5 patients developed severe urosepsis in the CON group. Compared with those in the CON group, the patients with postoperative urosepsis in the EXP group showed lower serum levels of IL-6 at postoperative hour two (p = 0.045) and at postoperative day one (p = 0.031) and lower serum levels of PCT at postoperative day one (p = 0.015). There was a better clinical outcome of a shorter postoperative hospital stay (p = 0.015) in patients with postoperative urosepsis in the EXP group than in those in the CON group.ConclusionThe perioperatively combined application of dexamethasone and furosemide was beneficial for alleviating postoperative inflammatory reaction and caused a better clinical outcome of a shorter postoperative hospital stay.

Correlation between inflammatory cytokines and liver cancer stem cell markers in DEN-induced liver cancer rats.

To study the association of inflammatory factors and hepatocarcinoma stem cells of induced liver cancer rats. 30 SD male healthy rats were selected. 10 rats were given water as normal control group. 10 rats only were implemented laparotomy as sham operation group. The remaining 10 rats were the liver cancer model group and treated with diethylnitrosamine (DEN) to induce liver cancer. Real-time quantitative PCR was used to detect the related inflammatory factors in HCC tissues, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-β1 (TGF-β), human interleukin-1α (IL-1α), human interleukin 1β (IL-1β) and levels of hepatocarcinoma stem cells indicators CD90, CD133, Alpha-fetoprotein (AFP). Correlation analysis was used to analyze the correlation between inflammatory factors and hepatocarcinoma stem cells markers CD90 and CD133. The expression levels of IL-6, MCP-1 and TGF-β of HCC tissues in liver cancer model group were significantly higher than those in the control group and the sham operation group. The expression levels of CD90 and CD133 of tissues in the liver cancer model group were significantly higher than those in the control group and the sham operation group. The differences were statistically significant (p<0.001). By inhibiting related inflammatory factors, the growth, migration and invasion of liver cancer cells were significantly inhibited, and apoptosis was promoted. Correlation analysis results showed that the expression changes of IL-6, MCP-1 and TGF-β were significantly positively correlated with CD90 up-regulation (p<0.05), while the expression changes of IL-6, MCP-1 and TGF-β were significantly positively correlated with CD133 up-regulation (p<0.05). The inflammatory factors IL-6, MCP-1 and TGF-β are closely related to hepatocarcinoma stem cells, which play an important role in promoting the occurrence and deterioration of liver cancer.

Combining Blood-Based Biomarkers to Predict Mortality of Sepsis at Arrival at the Emergency Department.

BackgroundOur aim was to determine a useful combination of blood biomarkers that can predict 28-day mortality of sepsis upon arrival at the Emergency Department (ED).Material/MethodsBased on Sepsis-3.0, 90 sepsis patients were enrolled and divided into survivor and nonsurvivor groups with day 28 as the study end point. After comparing the demographic data and clinical characteristics of patients, we evaluated the predictive validity of a combination of markers including interleukin-6 (IL-6), procalcitonin (PCT), and lactate at arrival at the ED. Independent risk factors were found by using univariate and multivariate logistic regression analyses, and the prognostic value of markers was determined by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve.ResultsThere were 67 (74.4%) survivors and 23 (25.6%) nonsurvivors. The levels of IL-6 (survivors vs nonsurvivors: median 205.30 vs 3499.00 pg/mL, P=0.012) and lactate (survivors vs nonsurvivors: median 2.37 vs 5.77 mmol/L, P=0.003) were significantly lower in survivor group compared with the nonsurvivor group. Markers including IL-6, PCT, lactate, and neutrophil-to-white blood cell ratio (NWR) were independent risk factors in predicting 28-day mortality due to sepsis. The combination of these 4 markers provided the best predictive performance for 28-day mortality of patients with sepsis, on arrival at the ED (AUC of 0.823, 95% confidence interval [CI] 0.723–0.924), and its accuracy, specificity, and sensitivity were 74.4% (95% CI 64.0–82.8%), 91% (95% CI 80.9–96.3%), and 65% (95% CI 42.8–82.8%), respectively.ConclusionsThe combination of IL-6, PCT, lactate, and NWR measurements is a potential predictor of 28-day mortality for patients with sepsis, at arrival at the ED. Further research is needed to confirm our findings.

Correlation of Serum BACE1 With Emergence Delirium in Postoperative Patients: A Preliminary Study.

Background: The mechanism underlying delirium, a common acute fluctuating mental state, may be related to the activation of a neuroinflammatory response. In this study, we attempted to investigate whether plasma inflammatory response markers, vascular and cerebrovascular injury-related markers, and neurodegeneration-associated markers were associated with emergence delirium (ED).Methods: Patients aged 50 years or above who underwent elective laparoscopic surgery under general anesthesia were included in this study. Delirium was assessed postoperatively with the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scale. Plasma samples were collected from ED patients and non-ED patients to test concentrations of inflammation markers, including interleukin 6 (IL-6), chitinase 3-like 1 (CHI3L1), S100 calcium-binding protein B (S100B), lipoprotein-associated phospholipase-A2 (Lp-PLA2), and macrophage migration inhibitory factor (MIF); vascular and cerebrovascular injury-related markers, including intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1); and neurodegeneration-associated markers, including alpha-synuclein (α-Syn) and β-secretase 1 (BACE1). Binary logistic regression analysis was performed to analyze the relationship between biomarkers and ED, and receiver operating characteristic (ROC) curves were used to analyze the diagnostic value of biomarkers.Results: A total of 104 patients were included in this study, with an average age of 63.69 ± 7.21. IL-6 (OR = 2.73, 95% CI: 1.66–6.44, P = 0.022), S100B (OR = 4.74, 95% CI: 1.88–11.95, P = 0.001), and BACE1 (OR = 6.54, 95% CI: 2.57–16.65, P < 0.000) were independent biological indicators for the occurrence of ED.CHI3L1, Lp-PLA2, MIF, ICAM-1, VCAM-1, and α-Syn were unrelated to ED. Plasma BACE1 level had a possible diagnostic value for ED [area under curve (AUC) = 0.75, 95% CI: 0.66–0.85], whereas plasma IL-6 (AUC = 0.62, 95% CI: 0.51–0.73) and S100B (AUC = 0.65, 95% CI: 0.54–0.76) levels had little diagnostic value for distinguishing ED vs. non-ED.Conclusion: Higher levels of systemic inflammation marker IL-6, cerebral inflammation marker S100B, and neurodegeneration-associated marker BACE1 are related to ED. Plasma BACE1 may be a potential diagnostic biomarker for ED.

High levels of interleukin-6 in patients with rheumatoid arthritis are associated with greater improvements in health-related quality of life for sarilumab compared with adalimumab

BackgroundIncreased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and have been shown to be predictive of therapeutic responses, fatigue, pain, and depression in patients with rheumatoid arthritis (RA), but limited data exist on associations between IL-6 levels and health-related quality of life (HRQoL). This post hoc analysis of MONARCH phase III randomized controlled trial data evaluated the potential of baseline IL-6 levels to differentially predict HRQoL improvements with sarilumab, a fully human monoclonal antibody directed against both soluble and membrane-bound IL-6 receptor α (anti-IL-6Rα) versus adalimumab, a tumor necrosis factor α inhibitor, both approved for treatment of active RA.MethodsBaseline serum IL-6 levels in 300/369 randomized patients were categorized into low (1.6–7.1 pg/mL), medium (7.2–39.5 pg/mL), and high (39.6–692.3 pg/mL) tertiles. HRQoL was measured at baseline and week (W)24 and W52 by Short Form 36 (SF-36) physical/mental component summary (PCS/MCS) and domain scores, Functional Assessment of Chronic Illness Therapy -fatigue, and duration of morning stiffness visual analog scale (AM-stiffness VAS). Linear regression of changes from baseline in HRQoL (IL-6 tertile, treatment, region as a stratification factor, and IL-6 tertile-by-treatment interaction as fixed effects) assessed predictivity of baseline IL-6 levels, with low tertile as reference. Pairwise comparisons of improvements between treatment groups were performed by tertile; least squares mean differences and 95% CIs were calculated. Similar analyses evaluated W24 patient-level response on minimum clinically important differences (MCID).ResultsAt baseline, patients with high versus medium or low IL-6 levels (n = 100, respectively) reported worse (nominal p < 0.05) SF-36 MCS and role-physical, bodily pain, social functioning, role-emotional domain, and AM-stiffness VAS scores. There was a greater treatment effect with sarilumab versus adalimumab in high tertile versus low tertile groups in SF-36 PCS, physical functioning domain, and AM-stiffness VAS (nominal interaction p < 0.05). PCS improvements ≥MCID were higher in high (odds ratio [OR] 6.31 [2.37, 16.81]) versus low (OR 0.97 [0.43, 2.16]) tertiles with sarilumab versus adalimumab (nominal interaction p < 0.05). Adverse events between IL-6 tertiles were similar.ConclusionsPatients with high baseline IL-6 levels reported better improvements in PCS, physical functioning domain, and AM-stiffness scores with sarilumab versus adalimumab and safety consistent with IL-6R blockade.Trial registrationNCT02332590. Registered on 5 January 2015

Identification of key modules and hub genes associated with lung function in idiopathic pulmonary fibrosis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease, characterized by a decline in lung function. To date, the pathophysiologic mechanisms associated with lung dysfunction remain unclear, and no effective therapy has been identified to improve lung function.MethodsIn the present study, we used weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes associated with lung function in IPF. Three datasets, containing clinical information, were downloaded from Gene Expression Omnibus. WGCNA was performed on the GSE32537 dataset. Differentially expressed gene s (DEGs) between IPF patients and healthy controls were also identified to filter hub genes. The relationship between hub genes and lung function was then validated using the GSE47460 and GSE24206 datasets.ResultsThe red module, containing 267 genes, was positively correlated with the St. George’s Respiratory Questionnaire score (r = 0.37, p < 0.001) and negatively correlated with the percent predicted forced vital capacity (FVC% predicted) (r = − 0.46, p < 0.001) and the percent predicted diffusion capacity of the lung for carbon monoxide (Dlco% predicted) (r = − 0.42, p < 0.001). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that the genes in the red module were primarily involved in inflammation and immune pathways. Based on Module Membership and Gene Significance, 32 candidate hub genes were selected in the red module to construct a protein-protein interaction network . Based on the identified DEGs and the degree of connectivity in the network, we identified three hub genes, including interleukin 6 (IL6), suppressor of cytokine signaling-3 (SOCS3), and serpin family E member 1 (SERPINE1). In the GSE47460 dataset, Spearman correlation coefficients between Dlco% predicted and expression levels of IL6, SERPINE1, SOCS3 were –0.32, –0.41, and –0.46, respectively. Spearman correlation coefficients between FVC% predicted and expression levels of IL6, SERPINE1, SOCS3 were –0.29, –0.33, and –0.27, respectively. In the GSE24206 dataset, all three hub genes were upregulated in patients with advanced IPF.ConclusionWe identified three hub genes that negatively correlated with the lung function of IPF patients. Our results provide insights into the pathogenesis underlying the progressive disruption of lung function, and the identified hub genes may serve as biomarkers and potential therapeutictargets for the treatment of IPF patients.

Papaverine Has Therapeutic Potential for Sepsis-Induced Neuropathy in Rats, Possibly via the Modulation of HMGB1-RAGE Axis and Its Antioxidant Prosperities

Aim Our aim was to investigate the possible neuroprotective properties of papaverine in sepsis-induced critical illness neuropathy (SCIN) through the evaluation of various inflammatory biochemical markers, including interleukin 6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α), and oxidative stress biomarkers, such as malondialdehyde (MDA) and lactic acid. Additionally, evaluation of the HMGB1/RAGE interactions in SCIN was another target of this research. Method To create a sepsis model, a procedure involving intraperitoneal injection of feces was performed on 48 rats. The rats were divided into four equal groups: sham operated, controls and those receiving 20 and 40 mg/kg/day papaverine. After five-day treatments, compound muscle action potential (CMAPs) with electroneuromyography (ENMG) was recorded in all rats. Following ENMG evaluations, the plasma levels of sRAGE, HMGB1, TNF-α, IL-6, CRP, MDA and lactic acid were measured. Results TNF-α, CRP, IL-6, HMGB1, MDA, and lactic acid levels were significantly elevated in the SCIN group, and sRAGE levels were significantly decreased. In recipients of papaverine (20 and 40 mg/kg) treatment, these biochemical findings were improved. Furthermore, electrophysiological findings also showed significant improvement in both 20 and 40 mg/kg papaverine treated groups. Conclusion Papaverine demonstrates neuroprotective effects in a rat model of SCIN. Considering its anti-inflammatory and antioxidant properties, papaverine’s neuroprotective effects possibly stem from the suppression of the RAGE-HMGB1 axis.

Study the Correlation between Serum level of Interlukin 6 and Lactate Dehydrogenase in Myeloma Patients at Stage III with Serum Creatinine and Calcium Level

Multiple myeloma (MM) still an incurable disease that require better recognition and more research. Many previous studies shown the interaction between myeloma cells and bone marrow stromal cells for the initiation and progression of multiple myeloma . Many chemokines and their receptors including interleukin-6 (IL-6) an play important roles in this interaction. The main purpose of this study is assess the serum level of IL-6 and Lactate dehydrogenase on stage-III of MM patients and healthy controls then Finding the correlation with creatinine and calcium levels. Serum level of IL-6 , Lactate Dehydrogenase , creatinine and calcium levels of (30) MM patients diagnosis at stage –III according to International staging System (ISS) were measurement. The results for these parameters compare with (30) age- and sex-matched healthy controls groups. The results were showed that the mean levels of IL-6 , Lactate dehydrogenase , creatinine and calcium (increased or decreased)high significant (p?0.001) when compared with healthy controls . The results of the study suggested the important role of chemokines including IL-6 in the progression of the disease and its relationship with some biochemical parameters , especially in the stage-III of the disease.

Tocilizumab Utilization for Coronavirus Disease 2019

Background The deterioration of patients with coronavirus disease 2019 (COVID-19) has been hypothesized to be due to cytokine release syndrome including interleukin-6 (IL-6). Tocilizumab (TCZ) is an IL-6 inhibitor that may be a potential therapy for COVID-19. Methods Patients hospitalized for COVID-19 and treated with TCZ between March 1, 2020, and March 26, 2020, at an academic medical center in New York City were described. Patients were categorized as severe illness or critical illness based on previously described definitions. Outcomes assessed included respiratory status improvement, laboratory values, discharge, or death. Results A total of 12 patients were included in this case series. Ten patients were classified as critical and 2 as severe. Eight (n = 6 critical and n = 2 severe) patients had improvements in respiratory symptoms after receiving TCZ and were discharged, but 4 patients expired despite receiving therapy. All patients had an elevation in IL-6 and C-reactive protein levels before TCZ treatment. After TCZ treatment, there was a significant decrease in C-reactive protein levels (P = 0.002) and an increase in aspartate aminotransferase (P = 0.18) and alanine aminotransferase (P = 0.006) levels. Patients who received TCZ treatment later in their hospitalization course had a poor outcome. Conclusions Tocilizumab may play a role in treating patients with COVID-19 with elevated IL-6 levels, who are classified as severely ill and treated early in their disease course. The risks of adverse events and economic burdens should also be evaluated.

Pengaruh Ekstrak Etanol Daun Kenikir (Cosmos caudatus) terhadap Kadar Glutathion Dan Interleukin 6 Serum Tikus Wistar Jantan yang Diberi Pakan Tinggi Kolesterol

Chronic dyslipidemia, especially in hypercholesterolemia, can directly disrupt endothelial cell function through increased formation of oxidized LDL which will stimulate an inflammatory response including interleukin 6 (IL-6) release. For this reason, it is necessary to have anti-inflammation that can reduce the effects of hypercholesterolemia on blood vessels. Polyphenols have anti-inflammatory effects and kenikir leaves are vegetables that are rich in polyphenols. This study aims to prove the effect of kenikir leaf (Cosmos caudatus) ethanol extract on IL-6 levels of serum of male Wistar rats fed high cholesterol. The method used is a true experimental study with a Post-test Only Control Group Design. Samples using 24 male rats were divided into 4 groups DS, DTK, Ss, and Cc. DTK, Ss and Cc groups were given high cholesterol feed for 20 weeks. In the 17th to 20th weeks the Ss group was given additional simvastatin and the Cc group was given an additional extract of Cosmos caudatus leaf. Whereas the DS group was only given standard feed for 20 weeks. After 20 weeks all rats in all four groups were examined serum GSH and IL-6 levels. The results showed the highest GSH serum levels average in Cc with p-value=0,016 but not different from Ss. IL-6 serum levels in DTK were higher than those of the other three groups and were significantly different with p-value=0,035. The difference occurs between DTK and DS, Ss and Cc, not different between DS, Ss and Cc. The ethanol extract of kenikir leaf influences the serum IL-6 levels of male Wistar rats fed high cholesterol.

Perfectionistic Cognitions and Interleukin‐6: The Moderating Role of Child Maltreatment

Research is beginning to establish that perfectionism (i.e., the need to be absolutely perfect accompanied by harsh self‐criticism) contributes to poorer health and early mortality. Although few studies have addressed any personality/immune system links, there is growing evidence that personality can influence immune system functioning by altering cytokine production. Yet, to our knowledge, no study has examined the effect of perfectionism on immunological functioning. According to the Perfectionism Diathesis‐Stress Model, the deleterious effects of perfectionism on health should be further exacerbated by adverse childhood experiences (ACEs) such as maltreatment. However, this contention has yet to be tested empirically. The aim of this multidisciplinary research was to test how perfectionism is related to inflammatory analytes and whether these associations were moderated by child maltreatment. This study included a sample of young adults from the Niagara Longitudinal Heart Study (NLHS). Blood samples were collected, and serum was used to analyze levels of various immune biomarkers including Interleukin‐6 (IL‐6). Participants completed a self‐reported questionnaire that included the Childhood Trust Events Survey to identify exposure to sexual, physical, and emotional abuse before 18 years of age. Positive responses were then summed to create a count from 0 to 3 types of exposure. The Perfectionistic Cognitions Inventory assessed perfectionism. Results from multiple regression using Andrew Haye’s Process in which log‐transformed IL‐6 was regressed on perfectionistic cognitions, child maltreatment, and the interaction between perfectionistic cognitions and child maltreatment indicated that the relationship between perfectionistic cognitions and IL‐6 was moderated by child maltreatment. Specifically, higher perfectionistic cognitions were related to higher levels of IL‐6 under conditions of higher maltreatment. In sum, findings indicate that perfectionistic cognitions are related to immune system functioning and specifically to higher levels of IL‐6 when participants have experienced high levels of child maltreatment. These results support the Perfectionism Diathesis‐Stress Model and may provide key insights into both early prevention and intervention efforts aimed at reducing the toll of perfectionism on health.Support or Funding InformationThe NLHS is funded by the Canadian Institutes of Health Research (CIHR #s 363774, 399332). DSM is supported by an Early Researcher Award (Ministry of Research and Innovation, Government of Ontario). ARRM is supported by the Ontario Graduate Scholarship (OGS) Program.

Study of the correlation between vitamin D status and cytokine levels in patients with Crohn's disease

Objective: To investigate the correlations of serum total 25-hydroxyvitamin D (T-25 (OH) D) levels with serum cytokine levels including interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor α (TNF-α) and Crohn's disease activity index (CDAI) in patients with Crohn's disease (CD). Methods: A total of 60 patients with CD admitted in Peking Union Medical College Hospital from April 2014 to March 2019 who completed the tests for serum T-25 (OH) D and cytokines (IL-6, IL-8 and/or TNF-α) were retrospectively enrolled. Clinical data were collected for analysis. Results: Among 60 CD patients, there were 46 male patients, and the age was (34±13) years. There were 16 patients (26.7%) in remission and 44 cases (73.3%) in active status. The T-25(OH)D level was (16.0±7.7)μg/L. The prevalence of vitamin D sufficiency, insufficiency and deficiency was 26.7%, 40.0% and 33.3%, respectively. Correlation analysis showed that serum T-25 (OH) D level was negatively correlated with CDAI (r=-0.363,P=0.004), IL-6 level (r=-0.360,P=0.007), hsCRP level(r=-0.272, P=0.043) and ESR level(r=-0.293, P=0.024), while positively correlated with serum Alb level(r=0.372, P=0.003)、Hb(r=0.330, P=0.010) and BMI(r=0.276, P=0.033).Twenty-three cases (52.3%) of active CD patients accompanied with infection had a lower level of serum T-25 (OH) D than those without infection [(12.55±7.17) vs (17.41±6.49)μg/L, P=0.023]. Conclusion: Serum T-25 (OH) D level was negatively correlated with CDAI, serum IL-6 level and inflammatory markers in patients with CD, and it was lower in active CD patients with infection than those without infection.

In Vitro Effects of Curcumin on Transforming Growth Factor-β-mediated Non-Smad Signaling Pathway, Oxidative Stress, and Pro-inflammatory Cytokines Production with Human Vascular Smooth Muscle Cells.

Transforming growth factor-β (TGF-β) induces pro-inflammatory cytokines expression including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) and these cytokines are associated with the development of atherosclerosis. Curcumin has anti-atherogenic effects and anti-inflammatory properties in the vascular wall, but the relative mechanisms are almost unknown. In the present study, we investigate the effect of curcumin on modulating the pro-inflammatory action of TGF-β in human vascular smooth muscle cells (VSMCs) and its molecular mechanisms. Cultured VSMCs were seeded into several groups: a control group (untreated group), a group treated with TGF-β, and several groups treated with TGF-β plus inhibitors. The cells were pre-treated with diphenyleneiodonium chloride, DPI, (20 μM), curcumin (5, 10 and 20 μM) and N-Acetyl-L-Cysteine, NAC, (10 mM) and then TGF-β (5 ng/mL) was added to the culture medium. The mRNA levels of IL-6 and TNF-α were detected by quantitative Real-Time Polymerase Chain Reaction. For monitoring the Smad2 linker region phosphorylation (pSmad2L), the western-blotting technique was applied and reactive oxygen species (ROS) generation was measured by utilizing 2',7'-dichlorofluorescein diacetate-based assay. TGF-β increased the mRNA expression of IL-6 (p=0.02 and p=0.001) and TNF-α (p =0.014 and p = 0.001) in a time-dependent manner, ROS production (p=0.03) and Smad2L phosphorylation (p=0.015). Pre-treatment with curcumin, DPI and NAC inhibited TGF-β-induced IL-6 (p=0.04) and TNF-α (p=0.001) mRNA expression, Smad2L phosphorylation (p=0.02) and ROS production (0.03). Pharmacological inhibition by Curcumin blocks TGF-β-induced ROS production, Smad2L phosphorylation, and IL-6 and TNF-α mRNA expression in human VSMCs.

Remodeling gut microbiota by Clostridium butyricum (C.butyricum) attenuates intestinal injury in burned mice.

The dysbiosis of gastrointestinal microbiome is an important reason for burn-induced intestinal injury. Clostridium butyricum (C.butyricum) and its production butyrate are beneficial for the homeostasis of intestinal microflora and suppression of inflammatory response. The roles of C.butyricum and butyrate in burn-induced intestinal injury were explored. The effects of oral administration of C.butyricum on intestinal injury were observed in burned mice. The skin surface of mice was exposed to 95 °C water to induce a burn injury. Then the intestinal microbiome structure, abundance of C.butyricum and level of butyrate were respectively observed. The correction between intestinal permeability indicated by FITC dextran level and abundance of C.butyricum or level of butyrate was analyzed. C.butyricum was cultured and orally administrated to burned mice. The levels of butyrate, FITC dextran and pro-inflammatory cytokines, including interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were respectively measured. Burn injury altered the intestinal microbiome structure of mice, and especially decreased the abundance of C.butyricum and level of butyrate. Both the abundance of C.butyricum and the level of butyrate were negatively correlated with the intestinal permeability. Oral administration of C.butyricum increased the level of butyrate, decreased levels of TNF-α and IL-6, and suppressed intestinal damage in burn-injured mice. Oral administration of C.butyricum significantly alleviated the intestinal damage induced by burn injury. The therapeutic effects of C.butyricum and butyrate on burn injury should be further explored, which deserves further investigation.

Hybrid Training System Improves Insulin Resistance in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Pilot Study.

Insulin resistance is associated with the progression of nonalcoholic fatty liver disease (NAFLD). Insulin resistance is regulated by various cytokines, including interleukin-6 (IL-6), a proinflammatory myokine, and selenoprotein P (SeP), a liver-derived secretory hepatokine. High levels of IL-6 and/or SeP have been shown to contribute to insulin resistance, and exercise is a first-line therapy for NAFLD. We have developed a hybrid training system (HTS): a neuromuscular electrical stimulation device to enhance exercise results. We aimed to investigate the effects of HTS on insulin resistance as well as serum IL-6 and SeP in patients with NAFLD. This is a randomized, single-blind (assessor), controlled trial. Subjects with NAFLD walked on a treadmill with or without HTS (9 subjects each) for 30 minutes three times a week for six weeks (HTS vs. control group; median age 45 vs. 45; male/female 5/4 vs. 6/3). We examined subjects before the first session and at the end of the final session. Serum SeP levels were measured by ELISA which measures the fragment of SeP. In the HTS group, HOMA-IR values were significantly reduced compared to the control group (Δ-0.71 vs. Δ0.05; P < 0.05). IL-6 and SeP levels in serum were also significantly reduced compared to that of the control group (IL-6; Δ-0.6 vs. Δ0.29 pg/mL; P < 0.05, SeP; Δ-1288.5 vs. Δ-435.4 ng/mL; P < 0.05, respectively). In conclusion, we propose that HTS improves insulin resistance by reducing serum IL-6 and SeP levels in patients with NAFLD.

Relationships of blood proinflammatory markers with psychological resilience and quality of life in civilian women with posttraumatic stress disorder

Individuals with posttraumatic stress disorder (PTSD) show low resilience and impaired quality of life (QOL). Accumulating evidence shows that PTSD is associated with increased inflammation. Studies suggest that inflammation can be a key mechanism underlying low resilience/QOL, but this relationship has been understudied in individuals with PTSD. Here, we investigated the association of blood proinflammatory markers with self-reported resilience and QOL in civilian women with PTSD. Fifty-six women with PTSD and 73 healthy control women participated in this study. Resilience was assessed using the Connor-Davidson Resilience Scale. QOL was assessed using the World Health Organization Quality of Life-BREF. Blood samples were collected for the measurement of three proinflammatory markers including interleukin-6 (IL-6), high-sensitivity tumor necrosis factor-α, and high-sensitivity C-reactive protein (hsCRP). Compared to controls, patients showed significantly higher IL-6 levels and lower resilience and QOL. In patients, IL-6 levels were significantly negatively correlated with resilience, and hsCRP levels were significantly negatively correlated with psychological QOL. These results show that increased levels of proinflammatory markers including IL-6 and hsCRP are associated with lower psychological resilience and QOL in PTSD patients. Our findings suggest that interventions and treatments targeting inflammation may aid in the recovery from PTSD and lead to better prognosis.