Higher Plasma Interleukin-6 Levels Research Articles

Plasma IL-1 and IL-6 Family Cytokines with Soluble Receptor Levels at Diagnosis in Head and Neck Squamous Cell Carcinoma: High Levels Predict Decreased Five-Year Disease-Specific and Overall Survival.

Activation of the acute-phase cascade (APC) has been correlated with outcomes in various cancers, including head and neck squamous cell carcinoma (HNSCC). Primary drivers of the APC are the cytokines within the interleukin-6 (IL-6) and IL-1 families. Plasma levels of IL-6 family cytokines/soluble receptors (IL-6, IL-27, IL-31, OSM, CNTF, soluble (s-)gp130, s-IL-6Rα) and IL-1 family members (IL-1RA, s-IL-33Rα) were determined at diagnosis for 87 human papillomavirus (HPV)-negative (-) HNSCC patients. We then studied the 5-year Disease-Specific Survival (DSS) and Overall Survival (OS). Increased plasma levels of IL-6 (p < 0.001/p < 0.001) (DSS/OS), IL-31 (p = 0.044/p = 0.07), IL-1RA (p = 0.004/p = 0.035), soluble (s)-IL-6Rα p = 0.022/p = 0.035), and s-gp130 (p = 0.007/p = 0.003) at diagnosis were predictors of both OS and DSS from HPV(-) HNSCC patients. The cytokine DSS/OS predictions were associated with TNM stage and smoking history, whereas the soluble receptors IL-6Rα, gp130, and IL33Rα more uniquely predicted DSS/OS. Clinically, IL-6 levels above 2.5 pg/mL yielded 75% specificity and 70% sensitivity for DSS. In conclusion, high plasma levels of IL-6, IL-31, and IL-1RA, as well as the soluble receptors IL-6Rα, gp130, and IL33Rα, predicted clinical outcome. This shows their potential as candidates for both general therapy and immune therapy stratification, as well as being future platforms for the development of new immunotherapy.

Low-grade systemic inflammation and left ventricular dysfunction in hypertensive compared to non-hypertensive hypertrophic cardiomyopathy

BackgroundArterial hypertension (HTN) is associated with excess mortality in hypertrophic cardiomyopathy (HCM), but underlying mechanisms are largely elusive. The objective of this study was to investigate the association between HTN and markers of left ventricular (LV) dysfunction and low-grade systemic inflammation in a HCM cohort. MethodsThis was a single-center cross-sectional case-control study comparing echocardiographic and plasma-derived indices of LV dysfunction and low-grade systemic inflammation between 30 adult patients with HCM and HTN (HTN+) and 30 sex- and age-matched HCM patients without HTN (HTN-). Echocardiographic measures were assessed using post-processing analyses by blinded investigators. ResultsMean age of the study population was 55.1 ± 10.4 years, 30% were women. Echocardiographic measures of systolic and diastolic dysfunction, including speckle-tracking derived parameters, did not differ between HTN+ and HTN-. Moreover, levels of N-terminal pro B-type natriuretic peptide were balanced between cases and controls. Compared with HTN-, HTN+ patients exhibited a higher white blood cell count [8.1 ± 1.8 109/l vs. 6.4 ± 1.6 109/l; p < 0.001] as well as higher plasma levels of interleukin-6 [2.8 pg/ml (2.0, 5.4) vs. 2.1 pg/ml (1.5, 3.4); p = 0.008] and high-sensitivity C-reactive protein [2.6 mg/l (1.4, 6.5) vs. 1.1 mg/l (0.9, 2.4); p = 0.004]. ConclusionThis study demonstrates that HTN is associated with indices of low-grade systemic inflammation among HCM patients. Moreover, this analysis indicates that the adverse impact of HTN in HCM patients is a consequence of systemic effects rather than alterations of cardiac function, as measures of LV systolic and diastolic dysfunction did not differ between HTN+ and HTN-.

Repeated use of 3,4-methylenedioxymethamphetamine is associated with the resilience in mice after chronic social defeat stress: A role of gut–microbiota–brain axis

3,4-Methylenedioxymethamphetamine (MDMA), the most widely used illicit compound worldwide, is the most attractive therapeutic drug for post-traumatic stress disorder (PTSD). Recent observational studies of US adults demonstrated that lifetime MDMA use was associated with lower risk of depression. Here, we examined whether repeated administration of MDMA can affect resilience versus susceptibility in mice exposed to chronic social defeat stress (CSDS). CSDS produced splenomegaly, anhedonia-like phenotype, and higher plasma levels of interleukin-6 (IL-6) in the saline-treated mice. In contrast, CSDS did not cause these changes in the MDMA-treated mice. Analysis of gut microbiome found several microbes altered between saline + CSDS group and MDMA + CSDS group. Untargeted metabolomics analysis showed that plasma levels of N-epsilon-methyl-L-lysine in the saline + CSDS group were significantly higher than those in the control and MDMA + CSDS groups. Interestingly, there were positive correlations between plasma IL-6 levels and the abundance of several microbes (or plasma N-epsilon-methyl-L-lysine) in the three groups. Furthermore, there were also positive correlations between the abundance of several microbes and N-epsilon-methyl-L-lysine in the three groups. In conclusion, these data suggest that repeated administration of MDMA might contribute to stress resilience in mice subjected to CSDS through gut–microbiota–brain axis.

Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting

Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.

Higher plasma IL-6 and PTX3 are associated with worse survival in left heart failure with pulmonary hypertension

IntroductionLeft heart failure (LHF) is commonly complicated by pulmonary hypertension (PH), increasing morbidity and mortality. The present study aimed to evaluate the prognostic value of inflammatory proteins in LHF with PH (LHF-PH). Materials and methodsThe levels of 65 plasma proteins, analysed with proximity extension assay, were compared between healthy controls (n = 20), patients with LHF-PH (n = 67) comprising both HFpEF-PH (n = 31) and HFrEF-PH (n = 36), and in a LHF subpopulation before and after heart transplantation (HT, n = 19). Haemodynamic parameters were measured using right heart catheterization. ResultsPlasma levels of Interleukin 6 (IL-6) and Pentraxin related protein PTX3 (PTX3) were elevated in LHF-PH vs. controls (p < 0.001), and these decreased after HT compared to before HT (p < 0.001). Plasma IL-6 and PTX3 correlated to elevated NT-proBNP (r = 0.44, p = 0.0002 and r = 0.4, p = 0.0009, respectively). Additionally, IL-6 correlated with mean pulmonary arterial pressure (r = 0.4, p = 0.0009) and mean right atrial pressure (r = 0.51, p < 0.0001). Higher levels of IL-6 and PTX3 were associated with worse survival rates in patients with LHF-PH (Log rank p < 0.01). DiscussionIn patients with LHF-PH, higher plasma levels of IL-6 and PTX3 were associated with worse survival rates. Future larger studies to validate and investigate the direct clinical applicability of IL-6 and PTX3 as potential prognostic biomarkers are encouraged.

Co-Occurrence of Interleukin-6 Receptor Asp358Ala Variant and High Plasma Levels of IL-6: An Evidence of IL-6 Trans-Signaling Activation in Deep Vein Thrombosis (DVT) Patients

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in several mechanisms, and the alteration of IL-6 signaling leads to the overactivation of various processes including immunity, inflammation, and hemostasis. Although IL-6 increase has been documented in venous thromboembolic diseases, the exact involvement of IL-6 signaling in deep vein thrombosis (DVT) has not been fully understood. Consequently, we investigated the involvement of IL-6 trans-signaling in inflammatory events occurring in DVT, focusing on the role of the interleukin-6 receptor (IL6-R) Asp358Ala variant. The circulating levels of IL-6, soluble IL6-R (sIL6-R), and soluble glycoprotein 130, as well as the Asp358Ala genotyping, were assessed in a consecutive cohort of DVT patients and healthy controls. The results indicated that IL-6 was higher in DVT compared to controls. Moreover, sIL6-R levels were strongly correlated to Asp358Ala variant in both groups, showing a high frequency of this mutation across all samples. Interestingly, our results showed a high frequency of both Asp358Ala mutation and raised IL-6 levels in DVT patients (OR = 21.32; p ≤ 0.01), highlighting that this mutation could explain the association between IL-6 overactivation and DVT outcome. Overall, this study represents a proof of concept for the targeting of IL-6 trans-signaling as a new strategy for the DVT adjuvant therapy.

A pilot study of plasma interleukin-6 and interleukin-27 in differential diagnosis of acute respiratory distress syndrome and neonatal respiratory distress syndrome in preterm infants

To study the significance of interleukin-6 (IL-6) and interleukin-27 (IL-27) in the differential diagnosis of acute respiratory distress syndrome (ARDS) and neonatal respiratory distress syndrome (NRDS) in preterm infants. The preterm infants with the manifestation of respiratory distress who were treated in the Neonatal Diagnosis and Treatment Center, Children's Hospital of Chongqing Medical University, from March to November 2021, were enrolled in this prospective study. According to the diagnosis results, they were divided into two groups: ARDS group (n=18) and NRDS group (n=20). ELISA was used to measure the plasma levels of IL-6 and IL-27. The receiver operating characteristic (ROC) curve was used to analyze the value of each index in the diagnosis of ARDS. The ARDS group had significantly higher plasma levels of IL-6 and IL-27 than the NRDS group (P<0.05). The ROC curve analysis showed that IL-6 had an area under the ROC curve (AUC) of 0.867 for the diagnosis of ARDS, with a sensitivity of 61.1% and a specificity of 95.0% at the cut-off value of 56.21 pg/mL. The ROC curve analysis also showed that IL-27 had an AUC of 0.881 for the diagnosis of ARDS, with a sensitivity of 83.3% and a specificity of 80.0% at the cut-off value of 135.8 pg/mL. Plasma IL-6 and IL-27 can be used as biological indicators for early differential diagnosis of ARDS and NRDS in preterm infants.

ROLE OF INTERLUEKIN – 6 AS A PROGNOSTIC MARKER IN COVID-19 PATIENTS IN A TERTIARY CARE CENTRE IN INDORE DISTRICT, STATE M.P.

Background: Coronavirus disease 2019 (COVID-19) has spread rapidly around the world since its emergence and has wreaked havoc globally. As hospitals around the world are being overwhelmed due to the COVID-19 pandemic, it is of utmost urgency to identify biomarkers which would accurately predict patient outcome at an early stage. Many studies suggested that numerous markers of inflammation like CRP, ESR, LDH, D-Dimer, Serum Ferritin and Interleukin -6 were found to be significantly elevated in patients with severe disease relative to patients with milder conditions. Amongst which IL-6 appears to be the most important driver of immune dysregulation and ARDS in Covid-19. According to known evidence, IL-6 is superior to CRP and other markers of inflammation in predicting respiratory failure in Covid-19 (1, 2].&#x0D; Method: All patients had a positive covid-19 Reverse Transcriptase Polymerase Chain Reaction (PCR) test results. Patients with the history of comorbidities such as Hypertension (HTN), Diabetes Mellitus (DM), Chronic Obstructive Pulmonary Disease (COPD), Asthama, Heart failure, Chronic renal Failure (CRF) were included. The clinical and laboratory findings including Haemoglobin, WBC counts, Differential Counts, Liver Function Tests, C-Reactive Protein (CRP), Ferritin and Interleukin -6 (IL-6) were obtained from the database. Results: A total of 50 patients were included in the study. The median age of study population was found to be 52.5 years. It was observed that there were significantly increased serum IL-6 levels as the age increased. The serum levels of both IL-6 and CRP were markedly increased in morbid patients. Higher plasma IL-6 levels translated to more severity (determined by of days of hospital stay, mechanical ventilation and mortality).&#x0D; Conclusion: This study proves that serum IL-6 level is an accurate and a reliable indicator in predicting the prognosis of the patients in terms of longer hospital stay ,greater need of mechanical ventilation, and/ or increased mortality.&#x0D; Keywords: IL-6&amp; Covid-Biomarkers.

Serum interleukin-6 levels are higher in old age subjects with Alzheimer’s dementia

Elevated interleukin-6 (IL-6) levels have been found positively associated with markers of physical frailty as well as identified as a potential biomarker of Alzheimer’s disease (AD). Thus, we explored the levels of plasma IL-6 at baseline in a cohort of older subjects with or without cognitive impairment, which results may have also implications for coronavirus disease 2019 (COVID-19) clinical management. This is a retrospective study including a cohort of over 60 years old-age subjects, 72 healthy controls, 95 mild cognitive impairment, and 73 AD were included in the study. Plasma IL-6 was measured in all subjects. The sample population included 240 subjects, mostly women with a mean age of 78.61±6.30 (range: 60-93) years. Age significantly correlated with IL-6 plasma levels (r=0.204, P=0.002) even after controlling by gender. No difference was found in body mass index (BMI), nutritional status (assessed by mini nutritional assessment), and comorbidity indices (cumulative illness rating scaleseverity and comorbidity index) among groups. Instead, IL-6 significantly differed, having patients affected by AD higher levels compared to the other groups. Final linear regression analysis showed that independently of age, gender, BMI, nutritional status, number of clinically relevant concomitant diseases, the diagnosis of AD was associated with higher IL-6 plasma levels. These data indicate that serum IL-6 is more elevated in AD, supporting that IL-6 may have also a potential role in response to COVID-19 in old age subjects with cognitive impairment.

Association Between SIRT1, Cytokines, and Metabolic Syndrome in Schizophrenia Patients With Olanzapine or Clozapine Monotherapy.

Objective: Previous studies consistently showed the interaction between Sirtuin 1 (SIRT1) and immune inflammation is significantly related to metabolic abnormalities, but their role in the pathogenesis of metabolic syndrome caused by second-generation antipsychotics (SGAs) in schizophrenia patients largely remains unknown. Hence, the present study aimed to fill this gap.Methods: A total of 54 schizophrenia patients with olanzapine or clozapine monotherapy [metabolic syndrome (MetS)/non-MetS patients, 27/27] and 67 healthy subjects were recruited in the present study. The Positive and Negative Syndrome Scale was used, and the plasma levels of SIRT1, interleukin 6 (IL-6), IL-8, IL-10, and tumor necrosis factor α (TNF-α) were measured.Results: The results showed that schizophrenia patients treated with olanzapine or clozapine (both MetS and non-MetS groups) had significantly higher plasma levels of IL-6, IL-10, and TNF-α compared to normal controls (all P < 0.05). Moreover, the MetS patients exhibited markedly lower plasma levels of SIRT1 and higher plasma levels of IL-6 than non-MetS patients and normal controls (all P < 0.05). However, there were no significant differences in IL-8 levels between groups. Our correlation analysis showed that SIRT1 was significantly correlated with diastolic blood pressure, triglyceride, and high-density lipoprotein cholesterol in schizophrenia patients. The stepwise logistic regression analysis further identified the IL-6 × SIRT1 (β = −0.463, t = 10.040, P = 0.002) as the influencing factor for the MetS in the patients.Conclusion: Our preliminary findings suggest that SIRT1 interacted with inflammatory cytokines associated with MetS in schizophrenia patients treated with SGA monotherapy.

Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve

BackgroundThe brain–gut–microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion.MethodsThe fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined.ResultsThe ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes.ConclusionsThese findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain–gut–microbiota axis participates in the pathogenesis of depression via the vagus nerve.

Betaine supplementation is associated with the resilience in mice after chronic social defeat stress: a role of brain–gut–microbiota axis

Background: The brain–gut–microbiota axis plays a role in the pathogenesis of stress-related psychiatric disorders; however, its role in the resilience versus susceptibility after stress remains unclear. Dietary nutrient betaine is suggested to affect the gut microbiome. Here, we examined whether betaine supplementation can affect anhedonia-like phenotype in mice subjected to chronic social defeat stress (CSDS).Methods: CSDS was performed during betaine supplementation. Sucrose preference test and 16S rRNA analysis of fecal samples were performed.Results: CSDS did not produce an anhedonia-like phenotype in the betaine-treated mice, but did induce an anhedonia-like phenotype in water-treated mice. Furthermore, CSDS treatment did not alter the plasma levels of interleukin-6 (IL-6) of betaine-treated mice whereas CSDS caused higher plasma levels of IL-6 in water-treated mice. Betaine supplementation ameliorated the abnormal diversity and composition of the microbiota in the host gut after CSDS. At the genus level, CSDS caused marked increases in the several bacteria of water-treated mice, but not betaine-treated mice. CSDS increased levels of short-chain fatty acids (i.e., succinic acid and acetic acid) in feces from water-treated mice, but not betaine-treated mice. Interestingly, there are positive correlations between short-chain fatty acids (i.e., succinic acid, acetic acid, butyric acid) and several bacteria among the groups.Limitations: Specific microbiome were not determined.Conclusions: These findings suggest that betaine supplementation contributed to resilience to anhedonia in mice subjected to CSDS through anti-inflammation action. Therefore, it is likely that betaine could be a prophylactic nutrient to prevent stress-related psychiatric disorders.

Impact of interlukin-6 on central obesity measures in women with polycystic ovarian syndrome

Our aim was to investigate the relationship between plasma interleukin-6 (IL-6) levels with different measures of central obesity among Saudi women with and without polycystic ovarian syndrome (PCOS). One hundred and sixty-four Saudi females, between 22 and 38 years of age, with and without PCOS were enrolled in this case-control study. Physical examination and laboratory tests were completed for every subject. 2/3 of the study population were obese. Fasting serum insulin, plasma IL-6 levels and insulin resistance show significant increase among POCS than the controls (p<.05). Based on linear regression analysis, C-reactive protein (hs-CRP) was the only independent predictor of plasma IL-6 levels, accounting for 4% of the variability in plasma IL-6 (β = 0.217, p=.005, 95% CI: 0.049–0.275). Coexistence of metabolic and inflammatory factors in PCOS females is accompanied by central obesity which overpowers the effect of insulin resistance, contributing to higher plasma levels of IL-6 and CRP.Impact statementWhat is already known on this subject? Polycystic ovary syndrome (PCOS) is a cluster of many cardiovascular risk factors, but is also known as an inflammatory condition. Insulin resistance and abdominal obesity are classic components of PCOS. High circulatory levels of inflammatory markers in PCOS patients have been reported but it remains unclear whether their elevation is related to PCOS itself, or are a function of abdominal adiposity.What the results of this study add? The relationship between plasma interleukin-6 levels and different measures of central obesity was investigated among Saudi women with and without PCOS. Elevations of proinflammatory cytokines and inflammatory markers were reported in PCOS patients independently of insulin resistance. It remains to be established whether the proinflammatory state in PCOS is primarily due to inflamed adipose tissue.What the implications are of these findings for clinical practice and/or further research? The present study demonstrates that coexistence of metabolic and inflammatory factors in PCOS females are accompanied by central obesity which overpowers the effect of insulin resistance, contributing to higher plasma levels of IL-6 and CRP. Future studies including a larger population are needed to investigate the mechanisms by which IL-6 and hs-CRP promote cardiovascular risk in PCOS patients.

Detection of postoperative plasma circulating tumour DNA and lack of CDX2 expression as markers of recurrence in patients with localised colon cancer

BackgroundColon cancer (CC) is a heterogeneous disease. Novel prognostic factors beyond pathological staging are required to accurately identify patients at higher risk of relapse. Integrating these new biological factors, such as plasma circulating tumour DNA (ctDNA), CDX2 staining, inflammation-associated cytokines and transcriptomic consensus molecular subtypes (CMS) classification, into a multimodal approach may improve our accuracy in determining risk of recurrence.MethodsOne hundred and fifty patients consecutively diagnosed with localised CC were prospectively enrolled in our study. ctDNA was tracked to detect minimal residual disease by droplet digital PCR. CDX2 expression was analysed by immunostaining. Plasma levels of cytokines potentially involved in disease progression were measured using ELISAs. A 96 custom gene panel for nCounter assay was used to classify CC into colorectal cancer assigner and CMS.ResultsMost patients were classified into CMS4 (37%) and CMS2 (28%), followed by CMS1 (20%) and CMS3 (15%) groups. CDX2-negative tumours were enriched in CMS1 and CMS4 subtypes. In univariable analysis, prognosis was influenced by primary tumour location, stage, vascular and perineural invasion together with high interleukin-6 plasma levels at baseline, tumours belonging to CMS 1 vs CMS2 +CMS3, ctDNA presence in plasma and CDX2 loss. However, only positive ctDNA in plasma samples (HR 13.64; p=0.002) and lack of CDX2 expression (HR 23.12; p=0.001) were found to be independent prognostic factors for disease-free survival in the multivariable model.ConclusionsctDNA detection after surgery and lack of CDX2 expression identified patients at very high risk of recurrence in localised CC.

Inflammatory Markers and Incidence of Hospitalization With Infection in Chronic Kidney Disease.

Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003-2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-β (TGF-β)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n=1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-β were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-β, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD.

Association between IL-6 and metabolic syndrome in schizophrenia patients treated with second-generation antipsychotics.

ObjectiveSecond-generation antipsychotics (SGAs) have a high risk of causing metabolic syndrome (MetS). There is accumulating evidence supporting the fact that the activation of inflammatory pathway contributes to the development of MetS and further aggravates cognitive impairment. This study aimed to investigate the relationship between interleukin-6 (IL-6), cognitive function, and MetS in schizophrenia patients treated with SGAs.MethodsOne hundred and seventy-four patients with schizophrenia using SGAs were divided into MetS and non-MetS group, based on the criteria of the National Cholesterol Education Program’s Adult Treatment Panel III. Cognitive function was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A total of 138 patients and 29 healthy controls were examined in the plasma IL-6 levels.ResultsThe prevalence of MetS in schizophrenia patients treated with SGAs was 33% in this study. There were no significant differences in cognitive functions (both RBANS total score and subscale score) between MetS and non-Mets patients (P>0.05). Patients with MetS had higher plasma levels of IL-6 compared to non-MetS patients (P=0.019). However, such difference was only found in male patients (male: P=0.012; female: P=0.513). The partial correlational analysis further showed that IL-6 levels were notably negative related to the HDL levels in male schizophrenia patients after age, years of education, body mass index (BMI), age of onset, total disease course, and equal dose of olanzapine were controlled (male: P=0.009; female: P=0.450). In addition, the multiple regression analysis (stepwise model) performed in the male patient subgroup showed that IL-6 (beta =−0.283, t=−2.492, P=0.015) was an independent contributor to the HDL levels. However, the IL-6 was not an independent contributor to the HDL levels in female patients.ConclusionOur findings provide evidence suggesting that the immune-inflammatory effect of IL-6 on SGAs-induced MetS may be in a gender manner.

Abstract 128: Amelioration of Ischemic Stroke Damage Through Inhibition of Interleukin-6 Signaling With Tocilizumab Requires Sex Specific Dosing

Introduction: Interleukin 6 (IL-6) is a proinflammatory cytokine. Higher plasma IL-6 levels in stroke patients are correlated with increased stroke severity and poor prognosis. Our work has shown that tocilizumab, an FDA approved drug that blocks the IL-6 receptor (IL-6R) significantly reduced acute and long-term brain infarct and atrophy in aged male mice after stroke. At the same dose, tocilizumab had no significant effect on stroke outcome in aged females. Methods: We utilized aged (18-20 month) C57BL/6J male (N= 27) and female (N= 30) mice to examine neuroprotection and behavioral deficits with treatment. Mice were randomly assigned into 4 groups of either stroke or sham and drug or IgG control treatment. Stroke was induced by 1 hour of transient right middle cerebral artery occlusion followed by reperfusion for 35 days. Four hours after the onset of ischemia mice were given an intraperitoneal injection of either tocilizumab (20mg/1kg) or an IgG control. Tests were conducted to evaluate motor, sensory and cognitive deficits. Another aged female cohort (N= 15) was used to assess tocilizumab efficacy at reducing infarct 3 days post stroke with a higher dose (100mg/1kg). Results: Soluble IL-6R expression, while equivalent at baseline, is significantly higher after stroke in aged female mice compared to males (P= 0.0070). Tocilizumab treatment reduced brain atrophy (P= 0.0120), mortality (P= 0.0239) and behavioral deficits in aged males on multiple behavior tests (P&lt; 0.05). Females did not show similar benefits at the same dose (20mg/1kg). A higher dose of tocilizumab (100mg/1kg) reduced brain infarct acutely in aged females 3 days post stroke (P= 0.0005). This affect at only the higher dose in females is likely related to the higher level of soluble IL-6R seen post stroke compared to males. Testing in human stroke patient plasma revealed that women, as in mice, had significantly higher soluble IL-6R level compared to men after stroke (P= 0.0047). Conclusion: These results support our hypothesis that inhibition of the IL-6 receptor can be a novel therapeutic approach for stroke treatment. The neuroprotective dose of tocilizumab is different in males and females, which helps to emphasize the importance of determining dosage efficacy in a sex-specific manner.

Plasma interleukin-6 and executive function in crack cocaine-dependent women

AimThe aim of this study was to investigate the association between plasma interleukin 6 (IL-6) levels and executive function (EF) in crack cocaine-dependent women. Methods42 crack cocaine-dependent women (CRACK) and 52 healthy women (CONTROL) were evaluated with respect to EF using the Wisconsin Card Sorting Test (WCST). Plasma IL-6 levels were quantitatively determined using the multiplexed cytometric bead assay. ResultsThe CRACK group had poor performance on WSCT scores (Non-perseverative Errors and Percent Conceptual Level Responses) and higher plasma IL-6 levels when compared with the CONTROL group. Furthermore, IL-6 was correlated with worsening of several WCST sub-scores and a linear regression model showed that IL-6 levels predicted worse cognitive flexibility within the CRACK group independently of intelligence quotient and education. ConclusionsThe results of this study indicated that low performances in EF task are associated with higher IL-6 levels in crack cocaine-dependent women. These data bolster previous works that link the cognitive decline observed in drug addicts with mechanisms of inflammation.

Activated factor IX, factor XI and tissue factor identify patients with permanent atrial fibrillation treated with warfarin who are at risk of ischemic stroke.

IntroductionPreviously, we have demonstrated that significant proportions of patients with various cardiovascular diseases have active tissue factor and active factor XIa in their plasma. In the current study, we evaluated active tissue factor and active factors (F)XI and FIX in plasma from patients with atrial fibrillation.Material and methodsIn 110 consecutive patients with permanent atrial fibrillation receiving warfarin, we determined active tissue factor, together with plasma FIXa and FXIa, using clotting assays by measuring the response to inhibitory monoclonal antibodies.ResultsSixteen (14.5%) patients had detectable active tissue factor and active FXIa, including 11 subjects with both factors, while FIXa was observed in 28 (25.7%) patients. The three positive groups did not differ from the patients without these factors with regard to demographic and clinical characteristics. Von Willebrand factor was higher in the active tissue factor-positive group (p < 0.0001) and FXIa-positive group (p = 0.0037). Individuals positive for active tissue factor and FXIa had higher plasma interleukin-6 levels (p = 0.0014 and 0.0322, respectively). The presence of active tissue factor, FXIa and FIXa in anticoagulated patients with permanent atrial fibrillation correlated with elevated von Willebrand factor and interleukin-6. During a 3-year follow-up, ischemic stroke (n = 12, 10.9%) occurred more commonly among atrial fibrillation patients who had circulating TF (p = 0.002) or FXIa (p = 0.013).ConclusionsThese data suggest that circulating active coagulation factors, in particular TF and FXIa, can be detected despite oral anticoagulation in a significant proportion of patients with atrial fibrillation, and could represent novel markers of persistent prothrombotic alterations predisposing to ischemic stroke.

Diabetic foot syndrome: Immune-inflammatory features as possible cardiovascular markers in diabetes.

Diabetic foot ulcerations have been extensively reported as vascular complications of diabetes mellitus associated with a high degree of morbidity and mortality. Diabetic foot syndrome (DFS), as defined by the World Health Organization, is an "ulceration of the foot (distally from the ankle and including the ankle) associated with neuropathy and different grades of ischemia and infection". Pathogenic events able to cause diabetic foot ulcers are multifactorial. Among the commonest causes of this pathogenic pathway it's possible to consider peripheral neuropathy, foot deformity, abnormal foot pressures, abnormal joint mobility, trauma, peripheral artery disease. Several studies reported how diabetic patients show a higher mortality rate compared to patients without diabetes and in particular these studies under filled how cardiovascular mortality and morbidity is 2-4 times higher among patients affected by type 2 diabetes mellitus. This higher degree of cardiovascular morbidity has been explained as due to the observed higher prevalence of major cardiovascular risk factor, of asymptomatic findings of cardiovascular diseases, and of prevalence and incidence of cardiovascular and cerebrovascular events in diabetic patients with foot complications. In diabetes a fundamental pathogenic pathway of most of vascular complications has been reported as linked to a complex interplay of inflammatory, metabolic and procoagulant variables. These pathogenetic aspects have a direct interplay with an insulin resistance, subsequent obesity, diabetes, hypertension, prothrombotic state and blood lipid disorder. Involvement of inflammatory markers such as IL-6 plasma levels and resistin in diabetic subjects as reported by Tuttolomondo et al confirmed the pathogenetic issue of the a "adipo-vascular" axis that may contribute to cardiovascular risk in patients with type 2 diabetes. This "adipo-vascular axis" in patients with type 2 diabetes has been reported as characterized by lower plasma levels of adiponectin and higher plasma levels of interleukin-6 thus linking foot ulcers pathogenesis to microvascular and inflammatory events. The purpose of this review is to highlight the immune inflammatory features of DFS and its possible role as a marker of cardiovascular risk in diabetes patients and to focus the management of major complications related to diabetes such as infections and peripheral arteriopathy.