Higher Interleukin-6 Levels Research Articles

High Interleukin-6 Levels Are Associated With Large-Artery Atherosclerotic Stroke.

Interleukins (ILs) play several critical roles in modulating the occurrence and development of atherosclerosis-related diseases. We aimed to investigate the associations between ILs and the diagnosis, progress, and functional outcome in patients with large-artery atherosclerotic (LAA) stroke. Plasma levels of IL-2, IL-4, IL-6, and IL-10 were measured within 24 hours after stroke in 181 patients with first-time LAA stroke and on admission in 181 age-matched and sex-matched controls. NIHSS scores were recorded at admission and on Day 1, Day 2, Day 3, Day 4, and Day 5 after the stroke. Functional outcome was measured by the modified Rankin Scale at 3 months after stroke. Subgroup analyses were compared based on short-term progress within 5 days (ΔNIHSS ≥3) and 3-month unfavorable outcome (modified Rankin Scale >2). Logistic regression analysis adjusted for relevant confounders was performed. IL-6 levels were higher in patients with LAA stroke than in controls [AOR (95% CI), 0.701 (95% CI 0.651-0.748, P <0.001], with an area under the receiver operating characteristic curve (AUC) of 0.701. Higher IL-6 levels were associated with short-term progression [AOR (95% CI), 1.070 (1.009, 1.135), P =0.025], with an AUC value of 0.720. Higher IL-6 levels were associated with unfavorable outcomes [AOR (95% CI), 1.075 (1.002, 1.153), P =0.040], with an AUC value of 0.658. No difference in IL-2, IL-4, or IL-10 was found between the groups. Plasma levels of IL-6 are higher in patients with LAA stroke and are independently associated with short-term progression and 3-month functional outcomes after stroke.

High levels of baseline serum IL-10 are associated with reduced clinical benefit from first-line immune checkpoint inhibitor therapy in advanced renal cell carcinoma.

Immune checkpoint inhibitor (ICI) became a standard treatment for advanced renal cell carcinoma (RCC). However, clinically valid biomarkers of therapeutic outcome are lacking. We investigated the role of interleukin-10 (IL-10) as a predictive biomarker for first-line ICI therapy in patients with advanced RCC. Baseline serum samples were prospectively collected and analyzed using a cytometric bead assay. Patients were divided into two groups according to their serum IL-10 levels using maximally selected rank statistics. A fraction (13.0%) of patients had high levels of serum IL-10 at baseline. High serum IL-10 levels (> 4.3 ng/mL) were associated with a significantly shorter progression-free (median: 5.2 months vs. not reached, P = 0.007) and overall survival (median: 13.9 months vs. not reached, P < 0.001). Multivariate Cox regression analysis confirmed the independent association between high serum IL-10 levels and poor survival outcomes. Effector cytokine production and the proliferative response of CD8+ T cells were significantly lower in patients with high serum IL-10 levels, who also had a shorter duration of response to first-line ICI therapy (4.6 months vs. not reached, P < 0.001). In conclusion, elevated serum IL-10 levels at baseline were associated with reduced clinical benefit from first-line ICI therapy in patients with advanced RCC.

Inflammasomes in breast cancer: the ignition spark of progression and resistance?

Inflammation and immune evasion are major key players in breast cancer (BC) progression. Recently, the FDA approved the use of anti-programmed death-ligand 1 antibody (anti-PD-L1) and phosphoinositide 3-kinase (PI3K) inhibitors against aggressive BC. Despite the paradigm shift in BC treatments, patients still suffer from resistance, recurrence and serious immune-related adverse events. These obstacles require unravelling of the hidden molecular contributors for such therapy failure hence yielding therapeutics that are at least as efficient yet safer. Inflammasome pathway is activated when the pattern recognition receptor senses danger signals (danger-associated molecular patterns) from damagedRdying cells or pathogen-associated molecular patterns found in microbes, leading to secretion of the active pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). It has been shown throughout numerous studies that inflammasome pathway enhanced invasion, metastasis, provoked BC progression and therapy resistance. Additionally, inflammasomes upregulated the proliferative index ki67 and enhanced PD-L1 expression leading to immunotherapy resistance. IL-1β contributed to significant decrease in oestrogen receptor levels and promoted BC chemo-resistance. High levels of IL-18 in sera of BC patients were associated with worst prognosis. Stimulation of purinergic receptors and modulation of adipokines in obese subjects activated inflammasomes that evoked radiotherapy resistance and BC progression. The micro RNA miR-223-3p attenuated the inflammasome over-expression leading to lowered tumour volume and lessened angiogenesis in BC. This review sheds the light on the molecular pathways of inflammasomes and their impacts in distinct BC subtypes. In addition, it highlights novel strategies in treatment and prevention of BC.

Cyathocotylidae spp and motile aeromonads co-infections in farmed Nile tilapia (Oreochromis niloticus) causing mass mortality.

Motile aeromonads, and Cyathocotylidaespp.co-infections were identified in farmed Nile tilapia(Oreochromis niloticus) which suffering from mortalities. Moribund fish showed signs of septicemia, skin irritations, and respiratory distress. A total of 150 O. niloticus specimens showing signs of disease were collected from the affected earthmen ponds and examined. Bacteriological examination of fish samples revealed infections with motile aeromonads species. Phenotypic characteristics and phylogenetic analysis of gyrB gene sequences of aeromonads isolates identified them as Aeromonas hydrophila (12.6%), A.sobria (12.6%), and A. caviae (30.4%). Aeromonads strains harbored some virulence genes: Aer (78.62%); Hyl (60.86%); laf-A (52.17%); and Act (47.82%). The antibiogram of aeromonads showed high resistance against tetracycline (73.9%), and gentamycin (65.2%), while a high sensitivity was noticed to ciprofloxacin (82.6%),and trimethoprim/sulfamethoxazole (60.86%). Parasitological examination of fish revealed the presence of Cyathocotylidae spp. encysted metacercaria (EMC). High levels of interleukin 6 (IL-6) and cluster of differentiation 4 (CD4) were noticed in fish with parasitic and bacterial co-infection compared to those with a single infection or non-infected. Experimentally infected fish with Aeromonas spp. showed septicemic signs similar to that noticed in naturally infected tilapia with variable cumulative mortality. The study is one of the earlier reports identifying as Cyathocotylidae spp., and motile aeromonads co-infections, and their link with the exaggerated tilapia mortality which will be of value for incorporating these pathogens in the necessary management strategies to protect fish health.

IL-8 Produced Via Bidirectional Communication Between Prostate Cancer and M2 Macrophages as a Potential Diagnostic and Prognostic Biomarker.

Owing to the mortality associated with metastatic prostate cancer and the shortcomings of the current parameters in predicting the disease prognosis, we require the identification of viable biomarkers, which would help in the diagnosis and prognosis of the disease. We aimed to determine whether the interleukin-8 level in the tumor microenvironment could serve as a potential clinical diagnostic marker and prognostic factor for prostate cancer. The migration assay of prostate cancer cells was performed in an in vitro co-culture model. Cell lines PC3 and DU145 were divided into two groups and co-cultured with M0 and M2 macrophages, respectively. We used reverse transcription-quantitative polymerase chain reaction to detect M2 macrophage marker expression levels. Immunohistochemistry analyses of tissue microarrays were performed to analyze the correlation between the increased expression of interleukin-8 and the prognosis of prostate cancer. A retrospective analysis based on 142 residual serum specimens was performed to analyze the level of interleukin-8. We observed that M2 macrophages promoted the migration of prostate cancer cells and significantly increased the concentrations of interleukin-8 in the co-culture supernatants. We observed increased expression of CD163 and interleukin-8 in prostate cancer tissues. Furthermore, the levels of interleukin-8 in the serum of prostate cancer patients were higher than those in healthy controls. Untreated patients had higher levels of interleukin-8, which could be a predictor of a higher metastasis rate. These results suggest that interleukin-8 produced via bidirectional communication between prostate cancer cells and M2 macrophages is a putative biomarker for prostate cancer diagnosis and treatment.

The value of age IgG and IL6 in estimating time of viral clearance in asymptomatic or mild patients with COVID-19.

The aim of this study was to investigate the relationship between Age, immunoglobin G (IgG), immunoglobin M (IgM), procalcitonin (PCT), and interleukin-6 (IL6), and the time to clear viral nucleic acids in asymptomatic and mild coronavirus disease 2019 (COVID-19) patients, as well as evaluated the predictive value of these biochemical indicators. We performed a retrospective analysis on 1,570 individuals who were admitted to Tianjin First Central Hospital and diagnosed with asymptomatic or mild cases. Laboratory data were collected, including age, gender, levels of IgG, IgM, PCT and IL6, as well as results of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) nucleic acid test. These data were statistically analyzed using SPSS software, version 24.0. The results indicated that among mild patients, Age, IgG, and the time to clear viral nucleic acids were higher than asymptomatic patients (p < 0.05). And the time to clear viral nucleic acids was significantly correlated with Age, IgG, IgM, PCT, and IL6 (p < 0.05), IgG (r = -0.445, p < 0.001) showed moderate correlations. Using logistic regression analysis, we identified older age, high IL6 levels, and low IgG levels were risk factors for nucleic acid clearance exceeding 14 days (p < 0.05). When combining these three indicators to predict the probability of nucleic acid clearance exceeding 14 days in the 1,570 patients, the AUROC was found to be 0.727. Age, IgG, and IL6 could potentially serve as useful predictors for nucleic acid clearance exceeding 14 days in asymptomatic and mild COVID-19 patients.

Assessment of Depression and Its Correlation with Serum Levels of Interleukin-6 in Patients on Maintenance Hemodialysis.

Depression is the most common psychiatric disorder in patients on hemodialysis. An imbalance between proinflammatory and anti-inflammatory cytokines is thought to play a role in the pathogenesis of depression in patients on dialysis. We undertook this study to assess the correlations of the proinflammatory cytokine interleukin 6 (IL-6) and the anti-inflammatory cytokine IL-10 with depression in patients on maintenance hemodialysis. This cross-sectional observational study was carried out at our hospital, a tertiary care referral government teaching hospital, over 2 years. Depression was assessed using the Becks Depression Inventory score. A higher cutoff of >16 was taken for a diagnosis of depression. Clinical, demographic, and laboratory parameters were analyzed. Cytokines were assessed using enzyme-linked immunosorbent assays. Eighty patients satisfied the inclusion criteria. The prevalence of depression in our study was 41.5%. Depression was more common in those who were unemployed and/or illiterate. Mild depression was found in patients from the upper-lower and lower-middle classes, but severe depression was seen in lower-economic classes. Serum levels of IL-6 showed a positive correlation with the severity of depression. Depression was common in patients on maintenance hemodialysis. High levels of serum IL-6 were observed in those with depression. Depression in patients on maintenance hemodialysis is associated with a considerable risk of mortality.

Utility of Serum Interleukine-6 Level in Empty Nose Syndrome.

Objectives: Empty nose syndrome (ENS), a complication resulting from surgical procedures on turbinate tissue, is characterized by paradoxical nasal obstruction with wide nasal airways. Patients with ENS often also experience psychiatric symptoms, and psychiatric disorder detection remains dependent on subjective evaluation. Objective biomarkers for mental status assessment in patients with ENS are unestablished. This study aimed to evaluate the role of serum interleukin-6 (IL-6) levels in the mental status of patients with ENS. Methods: Overall, 35 patients with ENS who underwent endonasal submucosal implantation surgery were prospectively included in the study. The Sino-Nasal Outcome Test-25 (SNOT-25), Empty Nose Syndrome 6-item Questionnaire (ENS6Q), Beck Anxiety Inventory (BAI), and Beck Depression Inventory-II (BDI-II) were used to assess the physical and psychiatric symptoms of these patients preoperatively, and 3, 6, and 12 months postoperatively. Serum IL-6 levels were analyzed 1 day before surgery. Results: All subjective assessments significantly improved 3 months after surgery and plateaued at 12 months. Patients with higher serum preoperative IL-6 levels tended to experience more severe depression. Regression analysis showed that a preoperative serum IL-6 level > 1.985 pg/mL was significantly correlated with severe depression status in patients with ENS (odds ratio = 9.76, p = 0.020). Conclusions: ENS patients with higher preoperative serum IL-6 levels were more likely to have severe depressive burden. Since more suicidal thoughts or attempts were noted in these patients, timely treatment plan for patients with high levels of serum IL-6 is crucial and may consider psychotherapy after surgical treatment.

Frailty of Prostate Cancer Patients Receiving Androgen Deprivation Therapy: A Scoping Review.

This study aimed to explore the existing literature on frailty experienced by patients with prostate cancer (PC) receiving androgen deprivation therapy (ADT). Database and manual searches were conducted to identify relevant studies published in English, with no limitation on the year of publication, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. Four databases-PubMed, Cochrane Library, EMBASE, and CINAHL-were used for database searches and reference lists, related journals, and Google Scholar were used for manual searches. A total of 12 studies were analyzed for this scoping review. Of these, only 2 were intervention studies, and 1 was a randomized controlled trial. Among the two intervention studies, the multidisciplinary intervention program, including psychological counseling, nutritional coaching, and supervised group physical exercise did not show significant improvement in frailty. In contrast, high-dose vitamin D supplementation significantly decreased frailty. The conceptual and operational definitions of frailty used in each study varied, and the most used one was mainly focused on physical functions. As a result of analyzing the other health-related variables associated with frailty in patients with PC receiving ADT, age, metastases, comorbidities, and incident falls were related to a high frailty level. As for the physiological index, high levels of C-reactive protein, and interleukin-6, and fibrinogen, low levels of total testosterone, lymphocyte count, and creatinine were associated with a high level of frailty. A few studies explored the relationship between psychological and cognitive variables and frailty. Further research related to frailty in patients with PC receiving ADT should be conducted, and effective interventions to manage frailty should be developed. Additionally, research that considers not only the physical domain of frailty but also the psychological, cognitive, and social domains needs to be conducted.

Clinical value of interleukin - 6 as a potential biomarker for bronchogenic carcinoma

Background: Interleukin - 6 is found to be involved in various cancer types but countable studies has investigated its role in cancer lung. Objectives: The purpose of this research was to assess Interleukin-6 levels in bronchoalveolar lavage (BAL) and serum of cases with cancer lung and cases with benign lung conditions, and to determine its diagnostic utility for cancer lung. Subjects and Methods: This prospective interventional analytic study was conducted 40 cases at the Chest Department of Tanta University Hospitals. Cases were divided into two distinct groups: Group 1 comprised twenty individuals with bronchogenic carcinoma, while Group 2 comprised twenty individuals with non-malignant lung illnesses with established causes. All cases received a clinical examination, demographic information, and standard investigations. Using ELISA, the expression of interleukin-6 in BAL and serum was analysed. Results: Interleukin-6 levels were elevated in the BAL and serum of cancer cases versus the control group. Interleukin-6 levels in BAL and serum were positively correlated with advanced clinical stages of cancer lung, as were Interleukin-6 levels in BAL and serum. Conclusions: High BAL Interleukin-6 levels were associated with advanced clinical stage of cancer lung and correlated positively with serum Interleukin-6 levels. BAL Interleukin-6 was determined to be a molecular biomarker for cancer lung diagnosis and prognosis based on its high sensitivity and specificity in detecting lung carcinoma.

A Web-Based Method for the Identification of IL6-Based Immunotoxicity in Vaccine Candidates.

Interleukin 6 (IL6) is a major pro-inflammatory cytokine that plays a pivotal role in both innate and adaptive immune responses. In the past, a number of studies reported that high level of IL6 promotes the proliferation of cancer, autoimmune disorders, and cytokine storm in COVID-19 patients. Thus, it is extremely important to identify and remove the antigenic regions from a therapeutic protein or vaccine candidate that may induce IL6-associated immunotoxicity. In order to overcome this challenge, our group has developed a computational tool, IL6pred, for discovering IL6-inducing peptides in a vaccine candidate. The aim of this chapter is to describe the potential applications and methodology of IL6pred. It sheds light on the prediction, designing, and scanning modules of IL6pred webserver and standalone package ( https://webs.iiitd.edu.in/raghava/il6pred/ ).

Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model

Higher levels of interleukin (IL)-6 and elevated neutrophil counts are consistently reported in the blood of patients with schizophrenia. Stressors during childhood and/or adolescence are major socioenvironmental risk factors for schizophrenia and may contribute to immune dysregulation. Previous studies using blood cytokines to stratify patients with schizophrenia suggest that only a subset presents a low-grade inflammatory state. However, these studies have not addressed whether environmental factors such as childhood maltreatment contributed to identifying inflammatory clusters. Moreover, a neutrophil-related mechanism (Neutrophil Extracellular Traps; NETs) central to both the initiation and chronicity of autoimmune and inflammatory diseases has never been investigated in psychiatry. Elevated NETs in schizophrenia may predispose patients to inflammatory and autoimmune diseases resulting in reduced life expectancy. We, therefore, investigated NETs as a novel mechanism and biological target in early schizophrenia and their role together with IL-6 and childhood maltreatment in identifying cluster subgroups. We found increased NETs in the plasma of patients with early schizophrenia (n = 78) compared to both their unaffected siblings (n = 25) and community controls (n = 78), irrespective of sex, body mass index, psychoactive drug use, or tobacco smoking. Increased NETs in patients were unrelated to antipsychotic treatment, which was further tested in vitro using fresh neutrophils. By applying unsupervised two-step clustering analysis, we integrated values of NETs, IL-6, and childhood maltreatment scores. We identified two main clusters; childhood maltreatment scores and NETs were the most important variables contributing to cluster separation (high-CL1 and low-CL2), while IL-6 was the least contributor. Patients allocated in the high-CL1 (61.5%) had significantly higher childhood maltreatment scores, NETs, and IL-6 levels than the remaining groups (patients low-CL2, siblings, and controls high-CL1 and low-CL2). We complemented these findings with a rat model based on stress exposure during adolescence that results in several schizophrenia-like changes in adulthood. We found that adolescent stressed rats had higher NETs and IL-6 levels in serum compared to non-stressed rats with a tendency to produce more NETs from the bone marrow. Altogether, this study brings a novel cellular-based mechanism in schizophrenia that, combined with early-stress, could be useful to identify subgroups for more personalised treatments.

Associations Between Dysfunctional Thoughts, Leisure Activities, and IL-6 in Caregivers of Family Members With Dementia.

Dementia caregiving is associated with negative physical health consequences, including inflammation processes. The objective of this study was to analyze the associations between dysfunctional thoughts, frequency of leisure activities, and interleukin 6 (IL-6) in a sample of dementia family caregivers. One hundred forty dementia caregivers participated in this cross-sectional study. The relationships among caregivers' dysfunctional thoughts, leisure activities, and IL-6 were adjusted for demographic characteristics, stressors, and physical and mental health indicators in a linear regression analysis. Higher levels of dysfunctional thoughts ( t = -2.02, p = .045) were significantly associated with lower frequency of leisure activities. In turn, lower frequency of leisure activities was significantly associated with higher levels of IL-6 ( t = -2.03, p = .045). Dysfunctional thoughts were no longer significantly associated with IL-6 levels when both dysfunctional thoughts and leisure activities were included in the same model ( t = 1.78, p = .076). A significant indirect effect was found for the association between higher levels of dysfunctional thoughts and higher levels of IL-6 (standardized indirect effect = 0.036, bootstrap standard error = 0.026, 95% confidence interval = 0.0001-0.1000) through its association with fewer leisure activities. Our findings suggest that the direct effect of caregivers' dysfunctional thoughts on IL-6 may be mediated by the impact on caregivers' frequency of leisure activities. Results suggest that training caregivers in reducing dysfunctional thoughts to thereby increase leisure activities may be useful in reducing inflammation.

Establishment of quantitative indicators for an efficient treatment on masticatory muscle pain.

Although several studies have investigated effective treatments for masticatory muscle pain (MMP), no unified conclusion has been drawn regarding the effectiveness of these treatments. This study aimed to define quantitative indicators for predicting the outcome of MMP treatment. In total, patients aged 20-70 years were recruited and divided into the MMP (n = 24) and control (n = 36) groups, based on the presence of MMP according to the Diagnostic Criteria for Temporomandibular Disorders. At pretreatment, the MMP group was assessed using quantitative indicators such as subjective pain levels, pain duration, graded chronic pain scale (GCPS), and perceived stress scale (PSS). Salivary alpha-amylase (sAA) and interleukin-6 (IL-6) levels were analyzed. The masticatory muscle palpation score and the range of mouth opening were measured. At posttreatment, subjective pain levels, mouth opening, and treatment/medication duration were examined. The PSS and sAA levels were assessed in the control group. sAA levels in the MMP group were significantly higher than those in the control group (p < .05). The masseter muscle palpation score (MPS) showed a positive correlation with IL-6 levels (ρ = 0.503, p < .05) and a negative correlation with nonsteroidal anti-inflammatory drug (NSAID) treatment period (ρ = -0.462, p < .05). The temporalis muscle palpation score (TPS) was positively correlated with pain duration and GCPS grade (ρ = 0.483, p < .05, and ρ = 0.445, p < .05, respectively). Treatment with NSAIDs was effective in the MMP group with high MPS and IL-6 levels, but not in the MMP group with high TPS, pain duration, and GCPS grade.

C-Reactive Protein, Interleukin-6, Trimethylamine-N-Oxide, Syndecan-1, Nitric Oxide, and Tumor Necrosis Factor Receptor-1 in Heart Failure with Preserved Versus Reduced Ejection Fraction: a Meta-Analysis.

The purpose of this review was to synthesize the evidence on non-traditional biomarkers from proteomic and metabolomic studies that may distinguish heart failure (HF) with preserved ejection fraction (HFpEF) from heart failure with reduced ejection fraction (HFrEF) and non-HF. Understanding the pathophysiology of HFpEF continues to be challenging. A number of inflammatory and metabolic biomarkers that have recently been suggested to be involved include C-reactive protein (CRP), interleukin-6 (IL-6), trimethylamine-N-oxide (TMAO), syndecan-1 (SDC-1), nitric oxide (NO), and tumor necrosis factor receptor-1 (TNFR-1). A systematic search was conducted using Medline, EMBASE, and Web of Science with search terms such as "HFpEF," "metabolomics," and "proteomics," and a meta-analysis was conducted. The results demonstrate significantly higher levels of TMAO, CRP, SDC-1, and IL-6 in HFpEF compared to controls without HF and significantly higher levels of TMAO and CRP in HFrEF compared to controls. The results further suggest that HFpEF might be distinguishable from HFrEF based on higher levels of IL-6 and lower levels of SDC-1 and NO. These data may reflect pathophysiological differences between HFpEF and HFrEF.

Neuro-Behcet's Disease Presenting as a Psuedotumoral Brainstem Mass: A Case Report

Objective Herein, we present a rare and diagnostically challenging case of neuro-Behcet disease (NBD) manifesting as a psuedotumoral brainstem mass. Background Psuedotumoral-NBD as a neurologic manifestation of Behcet's disease is rare. Imaging is characterized by mass-like lesions that enhance with contrast, are hyperintense with T2-weighted and fluid-attenuated inversion recovery (FLAIR) and show restricted diffusion. The differential includes glial lesions, lymphomas, infectious and granulomatous lesions. Design/Methods This is a case study of a 33-year-old male of West-African descent with a history of Behcet's disease. Results A 33-year-old male of West-African descent with a history of Behcet's disease, presented two years after his diagnosis with headaches, low-grade fever, genital ulcerations, and horizontal binocular diplopia. Imaging revealed a large right-sided T2/FLAIR hyperintense abnormality in the medulla with a central area of necrosis. Cerebrospinal fluid revealed lymphocytic-predominant pleocytosis with 11·106 cells/L (reference range 0-5), and high levels of interleukin-6. His vasculitis, infectious, paraneoplastic, flow cytometry, and autoimmune panels were negative. He tested positive for hepatitis-B core antigen, and latent tuberculosis. The etiology for his presentation was believed to be parenchymal NBD and he received a 3-day course of intravenous solumedrol (eventually transitioned to prednisone and azathioprine) with significant improvement. Imaging 1-week post-treatment revealed resolution of enhancement, and at 3 months he had near complete lesion resolution. Conclusions NBD can rarely present with a psuedotumoral presentation, which can cause diagnostic uncertainty. A thorough radiologic/laboratory workup should be conducted to exclude other neurologic diagnoses; however, a high index of suspicion for NBD is required in similar cases and a spectacular response to steroids are invaluable in diagnosis.

High Serum Levels of IL-6 Predict Poor Responses in Patients Treated with Pembrolizumab plus Axitinib for Advanced Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney malignancy worldwide with Pembrolizumab and axitinib treatment (Pembro/Axi) amongst the most effective first-line immunotherapies for advanced RCC. However, it remains difficult to predict treatment response and early resistance. Therefore, we evaluated whether baseline serum interleukin-6 (IL-6) could be a predictive biomarker. Between November 2019 and December 2021, 58 patients with advanced RCC were enrolled, administered first-line Pembro/Axi, and baseline blood samples were analyzed using flow cytometry. The mean baseline serum IL-6 concentration was 8.6 pg/mL in responders and 84.1 pg/mL in patients with progressive disease. The IL-6 cut-off value was set at 6.5 pg/mL using time-dependent receiver operating characteristic curves, with 37.9% of patients having high baseline serum IL-6 levels and 62.1% having low levels. Objective response rates were 58.3% and 36.4% in low and high IL-6 groups, respectively. Overall survival and progression-free survival were longer in patients with low IL-6 levels than in those with high levels. High IL-6 levels were related to reduced interferon-γ and tumor necrosis factor-α production from CD8+ T cells. Overall, high baseline serum IL-6 levels were associated with worse survival outcomes and reduced T-cell responses in Pembro/Axi-treated advanced RCC patients.

Assessing the variability and the role of inflammatory cytokines and monocyte chemoattractant protein-1 (MCP-1) in predicting stroke among hypertensives: A case-control study.

Atherosclerosis is a complex lipid-driven inflammatory disease in which numerous cell types and inflammatory mediators are involved in the progression of hypertension to stroke. Mediators' markers that could predict the progression of hypertension to stroke are of research importance. We assessed the predictive value of individual and combined cytokines and monocyte chemoattractant protein-1 (MCP-1) among hypertensives with or without stroke. In a case-control study, we enrolled 63 cases with stroke and hypertension (HPT-S), 59 stroke-free hypertensives (HPT), and 53 stroke free normotensives as controls (CS). Sociodemographic data and blood samples were collected for the estimation of Interleukin-10 (IL-10), IL-6, IL-8, IL-1β and monocyte chemoattractant protein-1 (MCP-1) using commercially available ELISA kits from Biobase Biotech, Shanghai, China. The Receiver Operator Characteristics (ROC) analysis was used to calculate diagnostic accuracy for cytokines in predicting stroke among hypertensives. A combined bioscore model of IL-10 and MCP-1 was generated to predict stroke among hypertensives. The multiple logistic regression analysis was used to assess the chances of IL-10 and MCP-1 in predicting stroke among hypertensives. Statistical analyses were performed using R-language. The HPT-S group had significantly higher levels of MCP-1 and IL-10 compared to the HPT and CS groups (p < 0.05). There was no significant difference in IL-1β, IL-8 and IL-6 amongst the three study groups. MCP-1 and IL-10 were predictive of stroke occurrence among hypertensives and were used to develop a bioscore model. An elevated MCP-1 and IL-10 with a bioscore 2 had a predictive accuracy of 0.81, a sensitivity of 0.77 and specificity of 0.84. At a bioscore of 1, the sensitivity and specificity for predicting stroke among hypertensives was 97.0% and 61.0% respectively. In a binary logistic regression, having a bioscore of 1 [aOR = 20.43, 95% CI (2.17-192.62), p = 0.008] or 2 [aOR = 26.00, 95% CI (2.92-231.31), p = 0.003] were significantly associated with stroke occurrence among hypertensives. Higher levels of IL-10 with a concomitant level of MCP-1 could serve as a good predictor of stroke among hypertensives. Subsequently, MCP-1 may prove useful as a therapeutic target for atherosclerosis in hypertensives. Combined bioscore of MCP-1 and IL-10 could serve as a good predictor of stroke among hypertensives.

Interleukin-6, infection and cardiovascular outcomes in acute heart failure: Findings from the EDIFICA registry.

Interleukin-6 (IL-6) is upregulated in response to infectious and inflammatory triggers and independently predicts all-cause mortality in acute heart failure (AHF). However, the association of IL-6 with cardiovascular outcomes and its interplay with C-reactive protein and infection, a major precipitating factor in AHF, remains poorly understood. The association between IL-6 and clinical outcomes (180days) in AHF was evaluated using a cohort of 164 patients from the EDIFICA registry. Median IL-6 levels at admission were 17.4pg/mL. Patients in the higher admission IL-6 tertile presented with lower blood pressure and more congestion, were diagnosed more frequently with infection, and had a longer hospital stay. Higher IL-6 levels were associated with increased risk of HF rehospitalization (hazard ratio per log₂ 3.69, 95% confidence interval (CI) 1.26-10.8, p=.017) and the composite of HF rehospitalization or cardiovascular death (hazard ratio per log₂ 3.50; 95% CI 1.28-9.57; p=.014), independently of major AHF prognosticators, including B-type natriuretic peptide and renal function. However, no independent associations were found for all-cause rehospitalization or mortality. Despite a moderate correlation of IL-6 with C-reactive protein (CRP) levels (R=.51), the latter were not associated with clinical outcomes in this population. IL-6 levels associate with higher rate of cardiovascular events in AHF, independently of classical prognosticators and evidence of infection, outperforming CRP as an inflammatory outcome biomarker.

Importance of IL-6 inhibition in prevention and treatment of antibody-mediated rejection in kidney allografts

Interleukin-6 (IL-6) is a cytokine critical for innate and adaptive immune responses. However, persistent expression of high levels of IL-6 are associated with a number of pathologic conditions including autoimmune diseases and capillary leak syndrome. Importantly, in kidney transplant patients, IL-6 may play a role in mediation of cell-mediated rejection (CMR) and antibody-mediated rejection (AMR). This is likely due to the importance of IL-6 in stimulating B cell responses with pathogenic donor-specific antibody (DSA) generation and stimulation of T effector cell responses while inhibiting T regulatory cells. Data from preliminary clinical trials and clinical observations show that tocilizumab (anti-IL-6R) and clazakizumab (anti-IL-6) may have promise in treatment of CMR, AMR and chronic (cAMR). This has led to a phase 3 placebo, randomized clinical trial of clazakizumab for treatment of cAMR, a condition for which there is currently no treatment. The identification of IL-6 production in vascular endothelia cells after alloimmune activation reveals another potential pathway for vasculitis as endothelia cell IL-6 may stimulate immune cell responses that are potentially inhibitable with anti-IL-6/IL-6R treatment. Importantly, anti-IL-6/IL-6R treatments have shown the ability to induce Treg and Breg cells in vivo which may have potential importance for prevention and treatment of DSA development and allograft rejection.