Increased Concentrations Of Interleukin-6 Research Articles

Mechanism of Extracellular Histone-Induced Endothelial Dysfunction Leading to Sepsis-Induced Acute Respiratory Distress Syndrome

Sepsis-induced acute respiratory distress syndrome (ARDS) is an independent risk factor for mortality in critically ill septic patients. However, effective therapeutic targets are still unavailable due to the lack of understanding of its unclear pathogenesis. With increasing understanding in the roles of circulating histones and endothelial dysfunction in sepsis, we aimed to investigate the mechanism of histone-induced endothelial dysfunction leading to sepsis-induced ARDS and to provide experimental support for histone-targeted treatment of sepsis-induced ARDS. First of all, in vitro experiments were conducted. Human umbilical vein endothelial cells (HUVEC) were stimulated with gradient concentrations of histones to explore for the optimal stimulation concentration in vitro. Then, HUVEC were exposed to histones at an optimal concentration with or without resatorvid (TAK-242), a selective inhibitor of Toll-like receptor 4 (TLR4), for 24 hours for modeling. The cells were divided into 4 groups: 1) the blank control group, 2) the blank control+TAK-242 intervention group, 3) the histone stimulation group, and 4) the histone+TAK-242 intervention group. HUVEC apoptosis was determined by flow cytometry, VE-Cadherin expression in endothelial cells was determined by Western blot, and the integrity of adhesion connections between endothelial cells was evaluated with confocal fluorescence microscopic images. Male C57BL/6 mice aged 6-8 weeks and weighing 22-25 g were used for the in vivo experiment. Then, the mice were given cecal ligation and puncture (CLP) as well as histone injection at 50 mg/kg via the tail vein for sepsis modeling. The experimental animals were divided into 6 groups: 1) the blank control group, 2) the blank control+TAK-242 intervention group, 3) the CLP model group, 4) the CLP+TAK-242 intervention group, 5) the histone model group, and 6) the histone+TAK-242 intervention group. After 24 h, the concentrations of serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined using ELISA kits. Western blot was performed to determine the expression of vascular endothelial (VE)-cadherin in the lung tissue. Hematoxylin and eosin (HE) staining was performed to observe the pathological changes in the lung tissue of the mice. Evans Blue was injected via the tail vein 30 min before the mice were sacrificed. Lung tissue was collected after the mice were sacrificed. Then, the concentrations of Evans blue dye per unit mass in the lung tissue from mice of different groups were evaluated, the rates of pulmonary endothelial leakage were calculated, and the integrity of the pulmonary endothelial barrier was evaluated. The results of the in vitro experiment showed that, compared with those of the control group, HUVEC apoptosis was significantly increased under histone stimulation (P<0.05), the expression of VE-cadherin was decreased (P<0.05), and the integrity of adherens junctions between endothelial cells was damaged. TAK-242 can significantly inhibit histone-induced HUVEC apoptosis and VE-cadherin expression reduction and maintain the integrity of adherens junctions between endothelial cells. According to the findings from the in vivo experiments, in mice with CLP-induced and histone-induced sepsis, TAK-242 effectively alleviated the increase in serum concentrations of IL-6 and TNF-α, reduced the downregulation of VE-cadherin expression in the lung tissue (P<0.05), decreased endothelial permeability of the lung vessels, and improved pathological injury in the lung tissue. By binding to TLR-4, histone decreases VE-cadherin expression on the surface of vascular endothelial cells, disrupts the integrity of intercellular adherens junctions, and triggers pathological damage to lung tissue. Using TLR-4 inhibitors can prevent sepsis-induced ARDS in histone-induced sepsis.

Acute Hormonal and Inflammatory Responses following Lower and Upper Body Resistance Exercises Performed to Volitional Failure.

This study aimed to investigate the effects of a single bench press (BP) vs. leg press (LP) resistance training sessions on testosterone, cortisol, C-reactive protein (CRP) interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) concentrations, and creatine kinase (CK) activity in strength-trained males. Eleven strength-trained males participated in a cross-over randomized trial, undergoing two experimental sessions each consisting of five sets of the BP or the LP exercise to volitional failure with a load corresponding to 50% of one-repetition maximum. Blood samples were taken at baseline (BA), immediately post (POST), and 1 h after the cessation of exercise (POST-1). A significant increase in IL-6 concentration from BA to POST-1 was observed during the LP condition (p = 0.004; effect size [ES] = 0.64). Additionally, a significant main effect of time was found for increasing testosterone concentrations from BA to POST exercise (p = 0.014; ES = 0.25). A significantly lower cortisol concentration at POST-1 compared to POST (p = 0.001; ES = 1.02) was noted in the BP condition. Furthermore, a significantly lower cortisol concentration was found at POST-1 in the BP compared to the LP condition (p = 0.022; ES = 1.3). A significant increase in CK activity was reported from BA to POST (p = 0.024; ES = 0.69) and POST-1 (p = 0.045; ES = 0.55) during the LP condition, and from BA to POST-1 (p = 0.014; ES = 0.96) during the BP condition. No significant differences were found in the CRP (p = 0.659) and TNF-α concentrations (p = 0.487). These results suggest that the amount of muscle mass engaged during the resistance exercise may influence the changes in IL-6 and cortisol concentrations. Larger muscle groups, as engaged in the LP, more likely lead to elevated concentrations of IL-6 myokine.

Association between dietary inflammatory potential and frailty is mediated by inflammation among patients with colorectal cancer: A cross-sectional study

Patients with colorectal cancer (CRC) are at high risk of frailty, leading to reduced quality of life and survival. Diet is associated with frailty in the elderly through regulating inflammation. Thus, we hypothesized that dietary inflammatory potential (as assessed by dietary inflammatory index [DII]) might be associated with frailty in patients with CRC through regulating inflammatory biomarkers. A total of 231 patients with CRC were included in this cross-sectional study. Dietary intake was evaluated by 3-day, 24-hour dietary recalls, and frailty status was assessed in accordance with the Fried frailty criteria. Plasma inflammatory cytokines were determined in 126 blood samples. A total of 67 patients (29.0%) were frail, with significantly higher DII scores than nonfrail patients, accompanied with significantly increased interleukin-6 (IL-6) and decreased interleukin-10 (IL-10) concentrations. Each 1-point increase of DII was related to a 25.0% increased risk of frailty. IL-6 was positively correlated with frailty and DII, whereas IL-10 was negatively correlated. After adjusting for age, sex, body mass index, education level, smoking status, and energy, mediation analysis revealed that the association between DII and frailty was significantly mediated by IL-6 (average causal mediation effect [ACME], 0.052; 95% confidence interval, 0.020–0.087; P = .002) and IL-10 (ACME, 0.025; 95% confidence interval, 0.004–0.063; P = .016). The ρ values for the sensitivity measure at which estimated ACMEs were zero were 0.3 and –0.2 for IL-6 and IL-10, respectively. Therefore, a pro-inflammatory diet was associated with frailty in patients with CRC possibly in part by affecting circulating IL-6 and IL-10 concentrations.

Интерлейкин-6 у больных пожилого и старческого возраста с трофическими язвами нижних конечностей

Aim. To study the pathogenetic role of interleukin-6 (IL-6) in old patients with trophic ulcers of the lower extremities. Methods. The study enrolled 66 patients suffered from trophic ulcers of the lower extremities. The mean age of study patients reached 77.1±9.1 years (62–97 years). The majority of patients (65.1%) were women. The concentration of IL-6 in the blood (n&lt;7.0 pg/ml) was determined by enzyme immunoassay. Results. Increased level of IL-6 was found in 77.3% of patients. The mean concentration of IL-6 was 14.9±14.6 pg/ml (1.5–288.6 pg/ml), median – 10.7pg/ml. The mean values of interleukin-6 in patients with venous ulcers reached 12.7 pg/ml, arterial – 13.4 pg/ml, mixed – 26.7 pg/ml (p=0.01). Direct correlation was registered between IL-6 level and the number of ulcers (r=0.3; p=0.02). There was a direct correlation between IL-6 concentration and the ulcers duration (r=0.28; p=0.03). There was a trend towards a direct correlation between interleukin-6 and ulcers size (r=0.23; p=0.08). In patients with infected ulcers, the mean IL-6 level was 17.5 pg/ml, in patients without microbiological growth – 11.6 pg/ml, but these differences did not reach the statistical significance (p=0.3). Significant direct correlations were established between IL-6 concentration and the level of C-reactive protein (r=0.61; p&lt;0.000001), leukocyte count (r=0.36; p=0.006), neutrophil count (r=0.39; p=0.002), platelet count (r=0.39; p=0.002), ESR (r=0.40; p=0.003), inverse correlation – with hemoglobin (r=-0.41; p=0.001). There was a direct correlation between IL-6 level and severity of frailty (r=-0.38; p=0.03) and inverse correlation – with instrumental activity in daily life scale (r=-0.35; p=0.03). Patients with elevated IL-6 concentration had higher CRP (18.3 and 6.7 mg/l; p=0.001) and ESR (42.5 and 28.1 mg/l; p=0.04mm/h), but lower hemoglobin levels (114.3 and 125.9 g/l; p=0.01). There was a tendency to a direct correlation between IL-6 level and the age of study patients (r=0.23; p=0.06). Conclusion. Study results indicate a frequent increase in the interleukin-6 level in old patients with trophic ulcers of lower extremities. An increase in IL-6 concentration is associated with number and duration of ulcers as well as with various hematological parameters.

Exercise-induced Hemolysis And Iron Regulation In Response To Mechanical Stress

Hepcidin, a liver derived hormone, plays a role in iron regulation due to decreases in iron absorption and/or iron recycling. Exercise-induced hepcidin secretion is thought to be augmented by increased interleukin-6 (IL-6) and hemolysis (i.e., disruption of red blood cells). However, it is difficult to comprehend the contributions of hemolysis during exercise for hepcidin secretion. PURPOSE: To investigate the impact of exercise-induced hemolysis by a drop jump with concomitant repetitions of mechanical stress on hepcidin response. METHODS: Ten healthy males attended in this study [means ± SD, age: 24 ± 3 yrs, height: 170.6 ± 5.8 cm, body weight: 64.4 ± 7.2 kg]. Participants conducted two trials on different days, consisting of drop jump exercise to induce mechanical stress (DJ trial) or without exercise (CON trial). DJ trial consists of 100 bouts of drop jump from a 60 cm box, and each jump was conducted with their maximal effort. Blood samples were collected before trials, immediately, 1 h, 2 h and 3 h after completion of trials. The timing of blood sampling in CON trial was matched with DJ trial. A p value less than 0.05 was considered statistically significant. RESULTS: Baseline serum ferritin concentration did not significantly differ between DJ (73.1 ± 42.8 ng/mL) and CON trials (65.2 ± 31.6 ng/mL, p = 0.135). Serum iron and myoglobin concentration significantly increased and serum haptoglobin concentrations significantly decreased post-exercise in DJ trial (p < 0.05). Plasma IL-6 concentration did not increase in either trial (p > 0.05). Serum hepcidin concentration significantly increased 3 h after both trials (p < 0.05); however, the relative increase in serum hepcidin concentrations did not differ significantly between DJ and CON trials (77.4 ± 70.6% vs. 39.1 ± 51.5%, p = 0.184). CONCLUSIONS: Hemolysis was occurred following the drop jump exercise, while post-exercise IL-6 and hepcidin elevations were not different between the trials. Mechanical stress-induced hemolysis may not be sufficient to induce hepcidin elevation without IL-6 changes.

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.

A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease.

There is increasing evidence for inflammation as a determinant in the pathogenesis of Parkinson’s disease, but its role in parkinsonian neurodegeneration remains elusive. It is not clear whether inflammatory cascades are causes or consequences of dopamine neuron death. In the present study, we aim to perform an in-depth statistical investigation of the causal relationship between inflammation and Parkinson’s disease using a two-sample Mendelian randomization design.Genetic instruments were selected using summary-level data from the largest genome-wide association studies to date (sample size ranging from 13 955 to 204 402 individuals) conducted on a European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist and tumour necrosis factor α. Genetic association data on Parkinson’s disease (56 306 cases and 1 417 791 controls) and age at onset of Parkinson’s disease (28 568 cases) were obtained from the International Parkinson’s Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10−8; F-statistic > 10) and independent (linkage disequilibrium r2 < 0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check the consistency of the findings.In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson’s disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = −2.364, 95% confidence interval (CI) = −4.789–0.060; years difference per 1 log-unit increase = −2.011, 95% CI = −3.706 to −0.317; years difference per 1 log-unit increase = −1.569, 95% CI = −2.891 to −0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson’s disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson’s disease or age at onset on any biomarkers of inflammation.We found evidence for a causal association between the onset of Parkinson’s disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson’s disease.

Similar inflammatory response and conduit artery vascular function between sexes following induced inflammation

What is the central question of this study? Are there sex differences in vascular function following induced inflammation when oestrogen is typically similar between sexes? What is the main finding and its importance? The present study suggests no sex differences in conduit artery vascular responses to acutely induced inflammation during the low-oestrogen phase of the menstrual cycle in premenopausal women. However, women exhibit lower microvascular function than men. Overall, the results underpin the role of oestrogen in previously observed sex differences and the importance of reporting the phase in the hormonal cycle when women are studied. Sex differences in cardiovascular disease incidence in premenopausal women and age-matched men have been attributed to the cardioprotective influence of oestrogen. However, limited knowledge exists regarding sex differences following acute inflammation when oestrogen concentrations are lower in women. We evaluated sex differences in vascular responses to induced inflammation when oestrogen concentrations are typically lower in women (early follicular phase or placebo phase of hormonal contraception). In 15 women and 14 men, interleukin-6 (IL-6) concentrations and vascular function [via brachial artery flow-mediated dilatation (FMD)] were assessed at baseline (BL) and 24 (24H) and 48hours (48H) after administration of influenza vaccine. After induction of inflammation, both sexes exhibited an increase in IL-6 concentrations at 24H [mean (SD) BL vs. 24H: women, 0.563 (0.50) vs. 1.141 (0.65) pg/ml; men, 0.385 (0.17) vs. 1.113 (0.69) pg/ml; P<0.05] that returned to near-baseline concentrations by 48H (BL vs. 48H, P>0.05). There were no sex differences in FMD, allometrically scaled FMD or IL-6 concentrations at any time point (P>0.05). Notably, women exhibited significantly lower microvascular function than men at every time point [P<0.05; reactive hyperaemic area under the curve (in arbitrary units): women, BL 35,512 (14,916), 24H 34,428 (14,292) and 48H 39,467 (13,936); men, BL 61,748 (27,324), 24H 75,028 (29,051) and 48H 59,532 (13,960)]. When oestrogen concentrations are typically lower in women, women exhibit a similar inflammatory response and conduit artery function, but lower microvascular response to reactive hyperaemia, in comparison to age-matched men.

Chronic Inflammation Mediates the Association between Cortisol and Hyperglycemia: Findings from the Cross-Sectional Population-Based KORA Age Study.

(1) Background: The study aimed to investigate the role of subclinical inflammation on the association between diurnal cortisol patterns and glycaemia in an aged population. (2) Methods: Salivary cortisol, interleukin-6 (IL-6) and glycated haemoglobin (HbA1c) were analysed in a sample of 394 men and 364 women (mean age = 5 ± 6.3, 65–90 years). The ratio of morning after awakening and late-night cortisol was calculated as an indication of diurnal cortisol slope (DCS). Multivariable regression models were run to examine whether IL-6 mediates the relationship between the DCS and glycaemia. The Sobel test and bootstrapping methods were used to quantify the mediation analyses. (3) Results: In comparison to normoglycaemic counterparts (n = 676, 89.2%), an increase in IL-6 concentrations, in individuals with hyperglycaemia (HbA1c ≥ 6.5%) (n = 82, 10.8%) (p = 0.04), was significantly associated with a flatter DCS. The link between flatter DCS and elevated HbA1c level was significant mediated by a heightened IL-6 level. Our results do not suggest reverse-directionality, whereby cortisol did not mediate the association of IL-6 with HbA1c. (4) Conclusions: In our sample, the relation between flatter DCS and hyperglycaemia was partly explained by IL-6 levels. The paradigm of subclinical inflammation-mediated cortisol response on glucose metabolism could have widespread implications for improving our understanding of the pathophysiology of type 2 diabetes mellitus.

Effect of oral alcohol administration on plasma cytokine concentrations in heavy drinking individuals

BackgroundAlcohol is known to modulate the immune system, including cytokines, under conditions of both acute consumption and chronic use. The specific pro- and anti-inflammatory effects and mechanisms whereby alcohol consumption modulates circulating cytokine concentrations are not well understood. Few studies in humans have investigated the effect of acute alcohol consumption on plasma cytokine concentrations in individuals who are heavy drinkers. MethodsData were pooled from two studies involving a total of 25 non-treatment seeking, heavy drinking individuals who undertook an oral alcohol administration procedure. Plasma cytokine [Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-18 (IL-18) and Tumor Necrosis Factor-alpha (TNF-α)] concentrations were measured at two baseline timepoints, then three hours after alcohol administration, and finally when breath alcohol concentrations returned to zero. Linear mixed models were conducted to determine whether there was a significant effect of time on cytokine concentrations. ResultsThere was a significant reduction in TNF-α concentration (F [3, 20.42] = 4.96, p = 0.01, η2p = 0.42) post alcohol administration, compared to baseline concentrations, and a significant increase in IL-6 concentrations (F [3, 27.81] = 9.06, p < 0.001, η2p = 0.49) post alcohol administration, compared to baseline. There were no significant changes in IL-18 or IL-10 concentrations. ConclusionsTo our knowledge, this is the first study to examine the acute effect of oral alcohol consumption on peripheral inflammatory markers in individuals with alcohol use disorder. Results indicate a clinically relevant increase in proinflammatory cytokines approximately 3 h after initial alcohol ingestion. Further research should be done to elucidate the complex interaction between alcohol and the immune system.

Role of interleukin-6 in human umbilical vein endothelial cell to mesenchymal cell transformation

Role of interleukin-6 in human umbilical vein endothelial cell to mesenchymal cell transformation

Effects of Vitamin D Status on Inflammatory Markers in Obese Subjects: A Systematic Review

Background: Recent studies have demonstrated the role of micronutrients in the manifestation of comorbidities associated with obesity. Vitamin D deficiency, in particular, appears to be associated with increased levels of inflammatory markers, which may lead to chronic low-grade inflammation, elevating the risk of chronic diseases such as diabetes, metabolic syndrome, and cardiovascular disease. The objective of this study was to perform a systematic review of observational studies conducted to investigate the effect of vitamin D deficiency on inflammatory markers in obese subjects. Methodology: This systematic review was conducted in accordance with the “STROBE” and PRISMA recommendations. Observational studies that evaluated the effect of vitamin D status on inflammatory markers in obese subjects were selected and reviewed. Searches were conducted in the PubMed, SciVerse Scopus, and Web of Science databases from February 21 to 22, 2018. Results: After the selection and removal of duplicate articles, 10 eligible articles were identified. Results from eight observational studies showed an association between vitamin D deficiency or insufficiency in the body and increased concentrations of inflammatory markers in obese individuals. On the other hand, two of the studies did not demonstrate any correlation. With regard to the inflammatory markers evaluated, eight studies showed high concentrations of ultra-sensitive C-reactive protein, five studies found an increase in interleukin-6 concentrations, and two studies noted increased levels of tumor necrosis factor. Conclusion: The data presented in this systematic review provide evidence of the association between vitamin D deficiency and increased inflammation in obesity.

Evaluation of Proinflammatory, NF-kappaB Dependent Cytokines: IL-1α, IL-6, IL-8, and TNF-α in Tissue Specimens and Saliva of Patients with Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders.

Background: Oral squamous cell carcinoma (OSCC) is a life-threatening disease. It could be preceded by oral potentially malignant disorders (OPMDs). It was confirmed that chronic inflammation can promote carcinogenesis. Cytokines play a crucial role in this process. The aim of the study was to evaluate interleukin-1alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α) in tissue specimens and saliva of patients with OSCC and OPMDs. Methods: Cytokines were evaluated in 60 tissue specimens of pathological lesions (OSCCs or OPMDs) and in 7 controls (normal oral mucosa, NOM) by immunohistochemistry and in saliva of 45 patients with OSCC or OPMDs and 9 controls (healthy volunteers) by enzyme-linked immunosorbent assays. Results: Immunohistochemical analysis revealed significantly higher expression of IL-8 in OSCC specimens and TNF-α in OSCCs and OPMDs with dysplasia as compared to NOM. Moreover, expression of TNF-α was significantly higher in oral leukoplakia and oral lichen planus without dysplasia, whereas expression of IL-8 only in oral leukoplakia without dysplasia in comparison with NOM. Salivary concentrations of all evaluated cytokines were significantly higher in patients with OSCC than in controls. Moreover, levels of IL-8 were significantly higher in saliva of patients with OPMDs with dysplasia as compared to controls and in OSCC patients as compared to patients with dysplastic lesions. There was also significant increase in salivary concentrations of IL-6, IL-8 and TNF-α in patients with OSCC as compared to patients with OPMDs without dysplasia. Conclusion: The study confirmed that proinflammatory, NF-kappaB dependent cytokines are involved in pathogenesis of OPMDs and OSCC. The most important biomarker of malignant transformation process within oral mucosa among all assessed cytokines seems to be IL-8. Further studies on a larger sample size are needed to corroborate these results.

Intraperitoneal neutrophils activated by KRAS-induced ovarian cancer exert antitumor effects by modulating adaptive immunity.

Increased neutrophil counts are a hallmark of a poor prognosis for cancer. We previously reported that KRAS promoted tumorigenesis and increased neutrophil counts in a mouse peritoneal cancer model. In the current study, we evaluated the role of increased neutrophils in cancer progression, as well as their influence on the intraperitoneal microenvironment. A mouse peritoneal cancer model was established using the KRAS-transduced mouse ovarian cancer cell line, ID8-KRAS. Neutrophil function was assessed by neutrophil depletion in ID8-KRAS mice. Neutrophil depletion markedly accelerated tumor formation; this was accompanied by an increase in interleukin-6 concentrations in ascites. Neutrophil depletion significantly decreased the amount of local and systemic CD8+ T cells, while increasing the amount of local CD4+ T cells, accompanied by an increased amount of monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) (P<0.05). The roles of peritoneal neutrophils (PENs) in CD8+ T cell activation were assessed in vitro. PENs of ID8-KRAS mice had a strong potential to enhance T cell proliferation with a higher expression of the T cell costimulatory molecules OX40 ligand (OX40L) and 4-1BB ligand (4-1BBL), as compared with peripheral blood neutrophils (PBNs). These findings suggest that neutrophils recruited into the KRAS-induced tumor microenvironment (TME) have antitumor properties with the potential to modulate the numbers of M-MDSCs and Tregs and activate CD8+ T cells through T cell costimulatory molecules.

Association between serum interleukin-6 concentrations and chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Background. Interleukin-6 (IL-6) is an important pro-inflammatory cytokine and has been implicated to play a role in the systemic inflammation of patients with chronic obstructive pulmonary disease (COPD). We conducted this meta-analysis to assess the association between serum IL-6 concentrations and COPD.Methods. PubMed and Embase were searched for eligible studies. Data were extracted by two investigators (Wei J, Xiong XF) independently and analyzed using Review Manager 5.3 and STATA 12.0 software. Standard mean differences (SMDs) and 95% confidence intervals (CI) were calculated.Results. Thirty-three studies were included in this meta-analysis. The serum IL-6 concentrations were higher in patients with stable COPD than healthy controls (SMD = 0.65, 95% CI [0.51–0.79]). COPD patients without major comorbidities also showed higher IL-6 levels than healthy controls (SMD = 0.74, 95% CI [0.56–0.91]). COPD patients with an forced expiratory volume in one second (FEV1) of either <50% predicted or >50% predicted had increased IL-6 concentrations compared to healthy controls (SMD = 0.77, 95% CI [0.48–1.05], SMD = 1.01, 95% CI [0.43–1.59], respectively). The serum IL-6 concentrations between mild-moderate and severe-very severe COPD patient groups were not found to be significant (SMD = −0.1, 95% CI [−0.65–0.44]).Conclusions. This meta-analysis indicated that patients with stable COPD had higher serum IL-6 concentrations than healthy controls. No evidence showing positive or negative association between IL-6 concentrations and the severity of pulmonary function impairment was found. The correlation between IL-6 levels and pulmonary function was weak in different severities of stable COPD patients.

Curcumin supplementation likely attenuates delayed onset muscle soreness (DOMS).

Oral curcumin decreases inflammatory cytokines and increases muscle regeneration in mice. To determine effects of curcumin on muscle damage, inflammation and delayed onset muscle soreness (DOMS) in humans. Seventeen men completed a double-blind randomized-controlled crossover trial to estimate the effects of oral curcumin supplementation (2.5 g twice daily) versus placebo on single-leg jump performance and DOMS following unaccustomed heavy eccentric exercise. Curcumin or placebo was taken 2 d before to 3 d after eccentric single-leg press exercise, separated by 14-d washout. Measurements were made at baseline, and 0, 24 and 48-h post-exercise comprising: (a) limb pain (1-10 cm visual analogue scale; VAS), (b) muscle swelling, (c) single-leg jump height, and (d) serum markers of muscle damage and inflammation. Standardized magnitude-based inference was used to define outcomes. At 24 and 48-h post-exercise, curcumin caused moderate-large reductions in pain during single-leg squat (VAS scale -1.4 to -1.7; 90 %CL: ±1.0), gluteal stretch (-1.0 to -1.9; ±0.9), squat jump (-1.5 to -1.1; ± 1.2) and small reductions in creatine kinase activity (-22-29 %; ±21-22 %). Associated with the pain reduction was a small increase in single-leg jump performance (15 %; 90 %CL ± 12 %). Curcumin increased interleukin-6 concentrations at 0-h (31 %; ±29 %) and 48-h (32 %; ±29 %) relative to baseline, but decreased IL-6 at 24-h relative to post-exercise (-20 %; ±18 %). Oral curcumin likely reduces pain associated with DOMS with some evidence for enhanced recovery of muscle performance. Further study is required on mechanisms and translational effects on sport or vocational performance.

Association Between Inflammatory Biomarkers and Bone Mineral Density in a Community‐Based Cohort of Men and Women

Based upon evidence in animal and in vitro studies, we tested the hypothesis that higher serum concentrations of the cytokines interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) and the inflammatory marker C-reactive protein (CRP) would be inversely associated with bone mineral density (BMD) in a community-based cohort of men and women, with the strongest associations among postmenopausal women not receiving menopause hormonal therapy (MHT). We ascertained fasting serum concentrations of IL-6, TNFα, and CRP and measured BMD at the femoral neck, trochanter, total femur, and spine (L2-L4) using dual x-ray absorptiometry in 2,915 members of the Framingham Offspring Study (1996-2001). We used multivariable linear regression to estimate the difference (β) in BMD at each bone site associated with a 1-unit increase in log-transformed serum concentrations of IL-6, TNFα, and CRP separately for men (n = 1,293), premenopausal women (n = 231), postmenopausal women receiving MHT (n = 498), and postmenopausal women not receiving MHT (n = 893). Inflammatory biomarkers were not associated with BMD in men. Among premenopausal women, there were statistically significant, modest inverse associations between IL-6 and trochanter BMD (β = -0.030, P < 0.01) and between CRP and femoral neck (β = -0.015, P = 0.05) and trochanter BMD (β = -0.014, P = 0.04). TNFα was positively associated with spine BMD (β = 0.043, P = 0.01). In postmenopausal women receiving MHT, CRP was positively associated with femoral neck BMD (β = 0.011, P = 0.04). There were no associations among postmenopausal women not receiving MHT. The lack of consistency in our results suggests that elevated circulating concentrations of inflammatory biomarkers may not be a risk factor for low BMD.

The Acute-Phase Response in Differentiating Sepsis from Inflammation in Neonates Who Require Abdominal Surgery

Introduction : In neonates, the influence of surgery on the inflammatory response has not been fully characterized and it remains difficult to differentiate an inflammatory response from sepsis. In this study, we evaluated changes in interleukin-6 (IL-6) and C-reactive protein (CRP) in neonates undergoing different major abdominal surgeries who had a normal postoperative course without infection.Material and Methods : In total, 43 neonates undergoing major abdominal surgery owing to congenital malformations involving the gastrointestinal tract, and who did not show blood culture positivity were enrolled in the study. As a control group, 40 neonates with proven sepsis were enrolled in the study over the same period. Blood samples for IL-6, CRP, and white blood cell count (WBC) determination were drawn before surgery and 48, 96, and 144 h [postoperative days (POD) 2, 4, and 6] after surgery.Results : There was a statistically significant increase in IL-6 concentrations on POD 2 compared with preoperative levels (p < 0.05). After POD 2, IL-6 levels decreased to preoperative levels. There was a statistically significant increase in CRP concentrations on POD 2, 4, and 6 (p < 0.05). Levels of CRP tended to be higher after surgery, and began to fall by the 6th day, but were still statistically higher than preoperative levels. In the sepsis group, CRP concentrations on day 6 were lower than in the surgery group (p < 0.05). White blood cell counts did not show statistically significant differences preoperatively versus postoperatively.Conclusions : In contrast to previous studies, our results show high levels of IL-6 on POD 2 and CRP on POD 6. It is important to differentiate between the diagnoses of sepsis and postoperative inflammation, because of the need to treat the infection. High levels of IL-6 and CRP are not always associated with sepsis after major abdominal surgeries, but may instead be associated with the inflammatory response and multiorgan dysfunction. Further studies are needed to better differentiate sepsis from inflammatory responses in patients undergoing other surgeries.

Free fatty acids are associated with insulin resistance but not coronary artery atherosclerosis in rheumatoid arthritis

BackgroundFree fatty acids (FFAs) affect insulin signaling and are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines such as interleukin-6 (IL-6) increase lipolysis and thus levels of FFAs. We hypothesized that increased IL-6 concentrations are associated with increased FFAs resulting in insulin resistance and atherosclerosis in rheumatoid arthritis (RA). MethodsClinical variables, serum FFAs and inflammatory cytokines, homeostasis model assessment for insulin resistance (HOMA-IR), and coronary artery calcium were measured in 166 patients with RA and 92 controls. We compared serum FFAs in RA and controls using Wilcoxon rank sum tests and further tested for multivariable association by adjusting for age, race, sex and BMI. Among patients with RA, we assessed the relationship between serum FFAs and inflammatory cytokines, HOMA-IR, and coronary artery calcium scores using Spearman correlation and multivariable regression analyses. ResultsSerum FFAs did not differ significantly in patients with RA and controls (0.56mmol/L [0.38–0.75] and 0.56mmol/L [0.45–0.70] respectively, p=0.75). Presence of metabolic syndrome was associated with significantly increased serum FFAs in both RA and controls (p=0.035 and p=0.025). In multivariable regression analysis that adjusted for age, race, sex and BMI, serum FFAs were associated with HOMA-IR (p=0.011), CRP (p=0.01), triglycerides (p=0.005) and Framingham risk score (p=0.048) in RA, but not with IL-6 (p=0.48) or coronary artery calcium score (p=0.62). ConclusionsSerum FFAs do not differ significantly in patients with RA and controls. FFAs may contribute to insulin resistance, but are not associated with IL-6 and coronary atherosclerosis in RA.

Associations between Markers of Liver Injury and Cytokine Markers for Insulin Sensitivity and Inflammation in Middle-Aged Japanese Men Not Being Treated for Metabolic Diseases

Elevated circulating alanine aminotransferase (ALT) and γ-glutamyltranspeptidase (γ-GTP) activities in healthy and preclinical subjects are associated with increased risk for obesity, diabetes and related complications. In the present study, we examined the associations between these hepatic enzymes and circulating cytokines as markers for insulin sensitivity (adiponectin) and inflammation [interleukin-6 (IL-6)] in middle-aged Japanese men not being treated for metabolic diseases. We conducted a cross-sectional study of 310 Japanese men aged 40-69 y (mean ± SD, 58.8 ± 7.6 y) who were not being treated for metabolic diseases and who participated in health checkups in Japan. We analyzed their lifestyle factors, clinical factors, and plasma adiponectin and IL-6 concentrations. We determined associations between the concentrations of these cytokines and the clinical and lifestyle factors using Spearman's correlation analysis, Jonckheere-Terpstra's test and multiple linear regression. ALT activity was negatively associated with adiponectin (r=-0.302, p<0.001) but not with IL-6. γ-GTP activity was positively associated with IL-6 (r=0.335, p<0.001) and negatively associated with adiponectin (r=-0.129, p<0.05). Aspartate aminotransferase (AST) activity was positively associated with IL-6 (r=0.131, p<0.05) and negatively associated with adiponectin (r=-0.125, p<0.05). Multiple linear regression analyses showed that adiponectin was independently and negatively associated with ALT activity, while IL-6 was independently and positively associated with γ-GTP activity. Adiponectin and IL-6 were not independently associated with AST activity. The results of this study indicate that circulating ALT activity is negatively associated with adiponectin concentration, γ-GTP is positively associated with increased IL-6 concentration, and AST is not associated with these cytokines in middle-aged Japanese men not being treated for metabolic diseases.