Role Of IL-6 Research Articles

Indicators of the cytokine profile and standard immunogram in the controlled and uncontrolled course of bronchial asthma in children

Bronchial asthma in children is a multifactorial disease, but it is based on atopic inflammation, which is the focus of the main methods of research and therapy of this pathology. However, if we evaluate not only the fact of the appearance of bronchial asthma in a particular patient, but also consider its course in more detail, and especially the possibility of achieving control over the disease, then indicators of not only atopic inflammation, but also local inflammation in general, acquire great influence, which is one of the reasons for the continuing high percentage of uncontrolled and partially controlled course bronchial asthma in children. The purpose of this work is to identify changes in cytokine status indicators and immunograms – markers of the risk of uncontrolled bronchial asthma. 167 patients with bronchial asthma were examined, who, based on a standard clinical and instrumental examination, according to the criteria of clinical recommendations, were divided into two groups – controlled (70 people) and partially controlled and uncontrolled (97 children). All of them had their cytokines and IgA, IgM, IgG, IgE levels determined, in blood serum by ELISA, subpopulations of lymphocytes by flow cytometry, indicators of neutrophilic phagocytosis by light microscopy. In the group with uncontrolled asthma, the following significant differences were noted: a decrease in the level of IL-7, IL-9 and an increase in IL-8, there is also a higher level of B lymphocytes, IgE and IgM, and a lower level of IgA, similar changes, but less pronounced, were previously detected in other studies when comparing patients with bronchial asthma and conditionally healthy, as well as mild and severe course diseases. There were no significant differences in the other studied indicators. It is noteworthy that the greater influence on the control of the disease in bronchial asthma is not exerted by atopic cytokines responsible for the very fact of atopic inflammation, but by cytokines of general inflammation, such as IL-7, IL-8, IL-9, regulating the severity of inflammation in general, the role of IL-8 as a cytokine of granulocyte chemotaxis regulating local inflammation is especially interesting.

Tumor-Activated Neutrophils Promote Lung Cancer Progression through the IL-8/PD-L1 Pathway.

Lung cancer remains a major global health threat due to its complex microenvironment, particularly the role of neutrophils, which are crucial for tumor development and immune evasion mechanisms. This study aimed to delve into the impact of lung cancer cell-conditioned media on neutrophil functions and their potential implications for lung cancer progression. Employing in vitro experimental models, this study has analyzed the effects of lung cancer cell-conditioned media on neutrophil IL-8 and IFN-γ secretion, apoptosis, PD-L1 expression, and T-cell proliferation by using techniques, such as ELISA, flow cytometry, immunofluorescence, and CFSE proliferation assay. The roles of IL-8/PD-L1 in regulating neutrophil functions were further explored using inhibitors for IL-8 and PD-L1. Lung cancer cell lines were found to secrete higher levels of IL-8 compared to normal lung epithelial cells. The conditioned media from lung cancer cells significantly reduced apoptosis in neutrophils, increased PD-L1 expression, and suppressed T-cell proliferation and IFN-γ secretion. These effects were partially reversed in the presence of IL-8 inhibitors in Tumor Tissue Culture Supernatants (TTCS), while being further enhanced by IL-8. Both apoptosis and PD-L1 expression in neutrophils demonstrated dose-dependency to TTCS. Additionally, CFSE proliferation assay results further confirmed the inhibitory effect of lung cancer cell-conditioned media on T-cell proliferation. This study has revealed lung cancer cell-conditioned media to modulate neutrophil functions through regulating factors, such as IL-8, thereby affecting immune regulation and tumor progression in the lung cancer microenvironment.

Role of Interleukins in Pancreatic Cancer: A Literature Review.

This review article summarizes the pathophysiological aspects of interleukins (ILs) including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in pancreatic cancer (PC). Science Direct, PubMed, and Google Scholar were used for the literature review. The search was conducted until August 12, 2024, and particular keywords such as "Pancreatic Cancer," "Interleukins," "Pathophysiological Aspects," "Immunosuppression," "Invasiveness," and "Metastasis" were used. Focusing on interleukins related to pancreatic cancer, 61 original studies were included: 32 studies for human patients, 16 studies for animal models, and 13 studies for both animal models and human patients. All types of PC were considered. The timeframe of 1991 to 2024 was chosen for clinical studies. In epithelial pancreatic tumors, IL-1 is a major inflammation factor. Serum concentrations of soluble interleukin-2-receptor were considerably greater in patients with PC and chronic pancreatitis than in healthy individuals. In comparison to controls, pancreatic cancer patients had considerably greater levels of macrophage colony-stimulating factor and significantly lower levels of stem cell factor and IL-3. The tissues and cells of pancreatic cancer have higher concentrations of IL-4 receptors. IL-5 has a role in the accumulation of pancreatic fibrosis. For individuals with pancreatic ductal adenocarcinoma (PDAC), a high serum level of IL-6 may be a separate risk factor for the development of widespread liver metastases. PDAC patients' peripheral blood mononuclear cells exhibit a substantial upregulation of IL-7 receptor. The role of IL-8 in the growth and spread of PC in humans. The miR-200a/β-catenin axis may be the mechanism by which IL-9 stimulates the proliferation and metastasis of PC cells. Blocking IL-10 in the local microenvironment appears to result in a significant reversal of tumor-induced immunosuppression. The article concludes that interleukins 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 played significant roles in the pathogenesis of PC.

Abstract 2365: Disrupting IL-11/IL-11R signaling by an efficacious anti-IL-11 antibody 9MW3811 enhances T cell tumor infiltration and synergizes with anti-PD-1 therapies in vivo

Abstract Background: IL-11 is known as an inflammation-related factor, and it has been proved to be a key driver in fibrotic diseases. Besides, the roles of IL-11 in tumor immunopathology were recognized more in-depth and comprehensively in recent years. IL-11 expression is highly and positively correlated with overall survival in various cancer types, including colorectal cancer, hepatocellular carcinoma and lung cancer. It was reported that IL-11 promoted tumor cell growth and metastasis, mediated partly through its direct effects on macrophages, T cells and cancer-associated fibroblasts. All these studies indicated that blocking IL-11 signaling may be a promising therapeutic approach for the treatment of solid tumors. In this report, 9MW3811, a high-affinity IL-11 blocking antibody was developed to test its anti-tumor activity and synergistic effects with anti-PD-1 antibody in mouse tumor models. Methods: 9MW3811 was generated by mouse hybridoma technology followed by antibody humanization and affinity maturation. Affinity of 9MW3811 was measured by Octet system. Its blocking activity of IL-11/IL11Ra/gp130 protein interaction was detected by ELISA, and the inhibiting effect of IL-11-mediated signaling was assessed with a luciferase reporter cell-based assay. In vivo efficacy of 9MW3811 was tested on A549 xenograft and LUSC PDX models. ScRNA-seq data collection and computational analysis were used to investigate immune cell tumor infiltration and differentiation. The synergistic tumor-suppressing effect of 9MW3811 with anti-PD-1 antibody was evaluated in MC38, CT26 and Hepa1-6 syngeneic models. Results: 9MW3811 showed sub-nanomolar binding affinity to recombinant and membrane bound IL-11 derived from human, mouse, rat and dog. 9MW3811 effectively blocked the formation of IL-11/IL-11R/gp130 protein complex, and inhibited the downstream cell signaling transduction. In the NSCLC A549 xenograft model, as compared with isotype control hIgG, 9MW3811 (2mpk) showed significant tumor growth inhibition (TGI 62%). In two LUSC PDX models, the TGIs for 9MW3811 (10 mpk) were 50% and 28%, respectively. Further, in MC38 and Hepa1-6 syngeneic models, 9MW3811 addition increased the TGI of anti-PD-1 antibody from 45% to 83%, and 34% to 75%, respectively. Interestingly, in an anti-PD-1 non-responsive CT26 model, the combo of 9MW3811/anti-PD-1 antibody exhibited an impressive antitumor activity (TGI 67%). Mechanistic study showed that treatment with 9MW3811 could significantly ameliorate T cell exhaustion, increase CD8+ T cells tumor infiltration and enhance the cytotoxic function of these infiltrated T cells by modulating the expression of a variety of cytokines/chemokines Conclusion: Our results demonstrated profound antitumor activity of 9MW3811 in different tumor models. 9MW3811 is currently in phase I clinical trials in AU, CN and US. Citation Format: Shuang Wang, Chang Zhang, Shasha Jiao, Dadi Zeng, Rongjuan Wang, Min Wang, Weining Lu, Bin Zheng, Xun Gui, Jinchao Zhang. Disrupting IL-11/IL-11R signaling by an efficacious anti-IL-11 antibody 9MW3811 enhances T cell tumor infiltration and synergizes with anti-PD-1 therapies in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2365.

Evaluation of Salivary Il-38 Levels in Periodontitis: A Cross-Sectional Study.

The goal of the current study was to assess levels of salivary interleukin (IL)-38, IL-1β, and IL-10 in various periodontal clinical conditions. In total, 60 (20 healthy, 20 gingivitis, and 20 stage II-III, grade A-B periodontitis) subjects were included in the study. Demographic and clinical periodontal parameters were recorded. Samples were examined for IL-38, IL-1β, and IL-10 levels by means of enzyme-linked immunosorbent assay. Results demonstrated that the periodontitis group had significantly lower salivary IL-38 levels (P < 0.05) than the healthy group. Salivary IL-10 levels did not differ significantly between the groups (P > 0.05). The salivary IL-1β levels of gingivitis (P < 0.001) and periodontitis groups (P < 0.01) were significantly higher than those of the healthy group. The present study indicated that IL-38 level is decreased in periodontal disease. The results suggested a possible role of IL-38 in the periodontal inflammation process. Clarifying the mechanisms of IL-38 in the inflammatory process may contribute to the development of novel treatment strategies in periodontal diseases.

Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer-An Exploratory Analysis of Clinical and Tumor Biological Significance.

Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC); the inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1β and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. The study included two independent cohorts of n = 92 and n = 102 patients who underwent a radical cystectomy for BC. Specimen from BC and benign urothelium (n = 22 and n = 39) were processed to a tissue microarray and immunohistochemically stained for IL-1β, IL-1RA, AKT, and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. An association with outcome was assessed using Wilcoxon Kruskal-Wallis tests, Chi-square tests or linear regression, dependent on the variable's category. Kaplan-Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Both IL-1β and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p < 0.005). IL-1β was associated with vascular invasion (210 vs. 183, p < 0.02), lymphatic invasion (210 vs. 180, <0.05) and G3 cancer (192 vs. 188, <0.04). The survival analysis revealed favorable RFS, CSS, and OS in the case of high IL-1β expression (p < 0.02, <0.03, and <0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1β expression on RFS, CSS, and OS. The IL-1β and IL-1β/IL-1RA ratios were positively correlated to the AKT expression (p < 0.05 and <0.01, respectively). Additionally, the high expression of Ki-67 (>15%) correlated with higher levels of IL-1β (p = 0.01). The overexpression of IL-1β and IL-1RA is frequently found in BC, with a prognostic significance observed for the IL-1β protein expression. The observed link between the IL-1β/IL-1RA axis and AKT signaling may indicate possible autophagy activation processes besides the known tumor-promoting effects of AKT.

Expression Analysis of Long Noncoding RNA-MALAT1 and Interleukin-6 in Inflammatory Bowel Disease Patients.

Inflammatory bowel disease (IBD) manifests as chronic inflammation within the gastrointestinal tract. The study focuses on a long noncoding RNA (lncRNA) known as Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1's misregulation has been linked with various autoimmune diseases and regulates proinflammatory cytokines. The role of IL6 in immune-triggered conditions, including IBD, is another focal point. In this research, the expression of MALAT1 and IL6 in IBD patients was meticulously analyzed to uncover potential interactions. The study involved 33 IBD patients (13 with Crohn's disease and 20 with ulcerative colitis) and 20 healthy counterparts. Quantitative real-time polymerase chain reaction determined the MALAT1 and IL6 gene expression levels. The competitive endogenous RNA (ceRNA) regulatory network was constructed using several tools, including LncRRIsearch and Cytoscape. A deep dive into the Inflammatory Bowel Disease database was undertaken to understand IL6's role in IBD. Drugs potentially targeting these genes were also pinpointed using DGIdb. Results indicated a notable elevation in the expression levels of MALAT1 and IL6 in IBD patients versus healthy controls. MALAT1 and IL6 did not show a direct linear correlation, but IL6could serve as MALAT1's target. Analyses unveiled interactions between MALAT1 and IL6, regulated by hsa-miR-202-3p, hsa-miR-1-3p, and has-miR-9-5p. IL6's pivotal role in IBD-associated inflammation, likely interacting with other cytokines, was accentuated. Moreover, potential drugs like CILOBRADINE for MALAT1 and SILTUXIMAB for IL6 were identified. This research underscored MALAT1 and IL6's potential value as targets in diagnosis and treatment for IBD patients.

Expression of the prognostic marker IL-8 correlates with the immune signature and epithelial-mesenchymal transition in breast cancer.

IL-8 has been implicated in the malignant progression of various types of cancers; however, the precise molecular mechanisms associated with IL-8 in breast cancer (BRCA) are unclear. We analyzed the clinical signature and immune characteristics of BRCA patients and its correlation with IL-8 expression using The Cancer Genome Atlas (TCGA) datasets. The role of IL-8 in epithelial-mesenchymal transition (EMT) was verified through Western blotting, Cell Counting Kit-8 assay, and wound healing assays, as well as cell invasion experiments. Through a comprehensive bioinformatics study, we determined that high IL-8 expression was associated with poor prognosis. Enrichment analysis revealed that high IL-8 expression was enriched in immune-related processes and cancer-related signaling pathways. In addition, IL-8 was associated with most of the immune-infiltrating cells, and high IL-8 expression indicated poor response to immunotherapy. Importantly, we found that IL-8 induced EMT in vitro. Taken together, our data indicate that IL-8 may be a potential and valuable prognostic marker in BRCA, which may induce adverse outcomes by modulating the immune response and promoting EMT in BRCA patients.

Interleukin 11 confers resistance to dextran sulfate sodium-induced colitis in mice

Intestinal homeostasis is tightly regulated by epithelial cells, leukocytes, and stromal cells, and its dysregulation is associated with inflammatory bowel diseases. Interleukin (IL)-11, a member of the IL-6 family of cytokines, is produced by inflammatory fibroblasts during acute colitis. However, the role of IL-11 in the development of colitis is still unclear. Herein, we showed that IL-11 ameliorated DSS-induced acute colitis in mouse models. We found that deletion of Il11ra1 or Il11 rendered mice highly susceptible to DSS-induced colitis compared to the respective control mice. The number of apoptotic epithelial cells was increased in DSS-treated Il11ra1- or Il11-deficient mice. Moreover, we showed that IL-11 production was regulated by reactive oxygen species (ROS) produced by lysozyme M-positive myeloid cells. These findings indicate that fibroblast-produced IL-11 plays an important role in protecting the mucosal epithelium in acute colitis. Myeloid cell-derived ROS contribute to the attenuation of colitis through the production of IL-11.

A Pan-Cancer Analysis of IRAK1 Expression and Their Association With Immunotherapy Response.

IRAK1 is an active kinase which plays a critical role in IL-1/TLR signaling pathway involved in inflammation and innate immune response. Recently, increasing evidence supports a potential role of IRAK1 in cancer progression. However, no immunological pan-cancer analysis of IRAK1 is available. We aimed to explore the prognostic value and the immunological functions of IRAK1. A series of datasets including The Cancer Genome Atlas, GEPIA2, cBioPortal, HPA, TIMER2.0 were performed to explore the oncogenic and immunological roles of IRAK1, including the relationship between IRAK1 and prognosis, genetic mutation, GO and KEGG enrichment pathway analysis, immune state of different tumors, The results showed that IRAK1 levels were upregulated in more than 20 types of cancers compared to the normal tissues. IRAK1 expression was associated with poorer prognosis in different cancer types. For the most frequent DNA alteration of IRAK1 is amplification. And the result of the enrichment analysis suggested that IRAK1 related to immune checkpoint pathway in cancer. IRAK1 inhibitor pacritinib inhibit proliferation and upregulate PD-L1 expression in different cancer cell lines. Moreover, the patients who receiving anti-PD-L1 therapy with low IRAK1 expression had a better prognosis, and the objective response rate to anti-PD-L1 therapy was higher in the low IRAK1 group than in the high IRAK1 group in IMvigor210 cohort. Our study reveals that IRAK1 can function as a prognostic marker in various malignant tumors. And pacritinib upregulated PD-L1 expression in several cancer cell lines, which indicating that IRAK1 can be used as a reliable marker to predict the efficacy of immunotherapy.

Phytoconstituents of Red Grape Seeds Extract as Inflammatory Modulator in Adjuvant Arthritic Rats: Role Of IL-1 and its Receptor Blocking

This study focused on investigating the phytochemical composition of the total extract and the ethyl acetate fraction of red grape (Vitis vinifera L.) seeds as well as evaluating the total extract as anti-arthritis agents in rats compering with the new treating agent; interleukin-1 receptor antagonist (IL-1RA) and the classical anti-inflammatory drug; indomethacin. HPLC and LC-ESI-MS analysis was applied for identification and quantification the flavonoid and phenolic compounds. Arthritis was induced by using complete Freund’s adjuvant (CFA). The percentages of edema as well as the arthritis index were evaluated on the 7th, 14th, 21th and 28th day post CFA-induction. The evaluation was done by measuring serum interleukin-1 beta (IL-1β), IL-1 receptor type I gene expression, oxidative stress markers, intracellular adhesion molecule-1 (ICAM-1), caspase-3 (cas-3), c-reactive protein (CRP), prostaglandin E2 (PGE2), total protein content, DNA fragmentation, chromosomal aberration and cytogenic damage. The histopathological features of the ankle joint were analyzed. Stilbenes, phenolic acids, and anthocyanins were the major identified classes in the ethyl acetate fraction, while flavan-3-ol, oligomeric and polymeric procyanidins, flavonoid glucosides and phenolic acids were the main categories in the total extract. Three major proanthocyanidin compounds; gallic-4-O-β-glucopyranoside, catechin 3,5-di-O-gallate and catechin 3-O-gallate were identified in the ethyl acetate fraction. Treatment with seeds extract and IL-1RA improved the selected parameters by variable degrees. IL-1 RA showed a pronounced treating effect. In conclusion, Vitis vinifera seeds extract and IL-1RA are considered as promising anti-arthritis agents. More studies are required to conduct Vitis vinifera seeds extract and IL-1RA in pharmacological and clinical applications.

Interleukin 8 and bronchial eosinophils in patients with asthma and cold airway hyperresponsiveness

Introduction. Cold airway hyperresponsiveness (CAHR) is common in patients with asthma. The effect of inhaled corticosteroid/long-acting β2-agonist therapy (ICS / LABA) on its severity, and the role of IL-8, and the eosino-philic profile of bronchial inflammation have not been studied. Aim. To study the dynamic relationship between the level of IL-8 and eosinophilic inflammation in the bronchi of asthma patients with CAHR using anti-inflammatory combined therapy with ICS / LABA. Materials and methods. Patients with asthma (n=59) received ICS / LABA for 24 weeks. The level of disease control (ACT, points), cellular composition of induced sputum (IS), bronchial response (ΔFEV1IHCA, %) to 3-minute isocapnic hyperventilation with cold (-20ºС) air (IHCA) was assessed. Exhaled breath condensate (EBC) was collected before and after the IHCA, in which the concentration of IL-8 (pg/mL) was determined. Results. Group 1 included 28 patients with CAHR (ΔFEV1IHCA = -14.1 ± 1.7%), group 2 included 31 patients with no response to cold bronchoprovocation (ΔFEV1IHCA = - 3.0 ± 2.4 %, p &lt; 0.0001). Initially, patients of groups 1 and 2 had no differences in ACT (16.8±0.6 and 15.7 ± 0.8 points), FEV1 (92.5 ± 3.6 and 87.8 ± 2.2%), the number of eosinophils in sputum (8.0 ± 2.4 and 4.7 ± 1.3%, respectively, p &gt; 0.05). The concentration of IL-8 before and after the IHCA test in group 1 was 131.2 ± 18.0 and 146.3 ± 23.5 pg/mL, respectively (p &gt; 0.05), in group 2 it was 130.5 ± 8.8 and 149.9 ± 18.4 pg/mL, respectively (p&gt;0.05). After treatment, the airway response to the IHCA significantly decreased in group 1 (ΔFEV1IHCA = - 8.8 ± 1.5 %, p &lt; 0.01), in group 2 it remained unchanged (- 3.6 ± 1.3 %, p &gt; 0.05). The level of asthma control in group 1 increased to 20.7 ± 1.6 ACT points (p &lt; 0.01), in group 2 – up to 19.7 ± 1.7 (p &lt; 0.05). The lung function did not change. After treatment, the level of IL-8 before and after the IHCA in group 1 did not change (89.8 ± 11.7 and 85.5 ± 7.8 pg/mL, p &gt; 0.05), as did the number of eosinophils (8.0 ± 2.4 and 6.2 ± 3.1 %, p &gt; 0.05). In group 2, the level of IL-8 before and after IHCA decreased from 89.2 ± 7.7 to 73.9 ± 10.3 pg/mL (p &lt; 0.01), the concentration of eosinophils decreased from 4.7 ± 1.3 up to 1.5 ± 0.57 % (p &lt; 0.05). Conclusion. 24-week therapy with ICS/LABA in patients with CAHR leads to improved asthma control, a decrease in the severity of cold bronchospasm, without being accompanied by changes in the level of IL-8, which affects the dynamics of the concentration of eosinophils in the bronchi.

Interleukins and Ischemic Stroke.

Ischemic stroke after cerebral artery occlusion is one of the major causes of chronic disability worldwide. Interleukins (ILs) play a bidirectional role in ischemic stroke through information transmission, activation and regulation of immune cells, mediating the activation, multiplication and differentiation of T and B cells and in the inflammatory reaction. Crosstalk between different ILs in different immune cells also impact the outcome of ischemic stroke. This overview is aimed to roughly discuss the multiple roles of ILs after ischemic stroke. The roles of IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-19, IL-21, IL-22, IL-23, IL-32, IL-33, IL-34, IL-37, and IL-38 in ischemic stroke were discussed in this review.

The role of IL-8 in the chronic airway inflammation and its research progress

Chronic rhinosinusitis（CRS）, asthma and chronic obstructive pulmonary disease（COPD） are common chronic airway inflammatory diseases, which seriously affect patients' quality of life and bring heavy economic and social burden. Interleukin（IL） -8 is an important chemokine of neutrophils and other inflammatory cells, which plays an important role in the development of chronic airway inflammation. In this review, the inflammatory mechanisms involved in regulating IL-8 gene expression and the role of IL-8 in different airway chronic inflammation were reviewed.

Neutralization of interleukin-38 exacerbates coxsackievirus B3-induced acute myocarditis in mice

BackgroundInterleukin (IL)-38, a novel member of the IL-1 family, has been reported to be involved in several diseases associated with viral infection. However, the expression and functional role of IL-38 in acute viral myocarditis (AVMC) have not been investigated.MethodsMale BALB/c mice were treated with intraperitoneal (i.p.) injection of coxsackievirus B3 (CVB3) for establishing AVMC models. On day 7 post-injection, the expression of IL-38 and IL-36R (IL-36 receptor) were measured. Mice were then treated with i.p. injection of mouse Anti-IL-38 Antibodies (Abs) for neutralization of IL-38. The survival, bodyweight loss, cardiac function, and myocarditis severity of mice were recorded. The percentages of splenic Th1 and Th17 cells, the expression levels of Th1/Th17-related master transcription factors (T-bet and RORγt) and cytokines were determined by flow cytometry, RT-qPCR, and ELISA, respectively. Cardiac viral replication was further detected.ResultsThe mRNA and protein expression levels of IL-38 in myocardium and serum, as well as cardiac IL-36R mRNA levels were significantly elevated in mice with AVMC. Increased IL-38 levels were negatively correlated with the severity of AVMC. Neutralization of IL-38 exacerbated CVB3-induced AVMC, as verified by the lower survival rate, impaired cardiac function, continuous bodyweight loss, and higher values of HW/BW and cardiac pathological scores. In addition, neutralization of IL-38 suppressed Th1 cells differentiation while promoted Th17 cells differentiation, accompanied by decreased T-bet mRNA expression and increased RORγt expression. Down-regulation of IFN-γ and up-regulation of IL-17, TNF-α, and IL-6 mRNA and protein expression levels in myocardium and serum were also observed in the IL-38 neutralization group. Furthermore, neutralization of IL-38 markedly promoted cardiac viral replication.ConclusionsNeutralization of IL-38 exacerbates CVB3-induced AVMC in mice, which may be attributable to the imbalance of Th1/Th17 cells and increased CVB3 replication. Thus, IL-38 can be considered as a potential therapeutic target for AVMC.

S733 Novel Cytokine Signature Predicts Acute Intestinal Inflammation Identified on Magnetic Resonance Enterography in Crohn’s Disease: A Role for IL-8, IL-10, IP-10, and MCP

S733 Novel Cytokine Signature Predicts Acute Intestinal Inflammation Identified on Magnetic Resonance Enterography in Crohn’s Disease: A Role for IL-8, IL-10, IP-10, and MCP

Roles of IL-8 -251A/T and +781C/T polymorphisms, IL-8 level, and the risk of age-related macular degeneration.

To clarify the association between IL-8 gene polymorphisms, IL-8 level, towards the risk of age-related macular degeneration (AMD). Meta-analysis was performed from available studies that investigated IL-8 -251A/T (rs4073) and +781C/T (rs2227306) polymorphisms and IL-8 levels in patients with AMD and controls. Overall, the pooled result showed a significant association between AMD with allelic (T vs. C; OR 1.53; p = 0.005), dominant (TT + CT vs. CC; OR 1.95; p = 0.017), homozygous (TT vs. CC; OR 2.03; p = 0.039) and heterozygous (CT vs. CC; OR 1.92; p = 0.032) models of rs2227306; while subgroup analysis revealed a significant association between rs2227306 with wet AMD in allelic (T vs. C; OR 1.69; p = 0.016), recessive (TT vs. CT + CC; OR 1.81; p = 0.00007), and homozygous (TT vs. CC; OR 2.64; p = 0.003) models. No significant association was observed between rs4073 with AMD in all inheritance models. In parallel, patients with AMD, particularly wet AMD had an elevated level of IL-8 compared to control. This meta-analysis suggests that patients with AMD or wet AMD have higher IL-8 levels compared to control, which is also supported by the evidence that carrier T allele of rs2227306 exhibited an increase in the risk of AMD or wet AMD. Thus, IL-8 +781C/T (rs2227306) polymorphism and the level of intraocular IL-8 may be useful as a biomarker for early detection and a therapeutic target of AMD.

Monocyte-dependent co-stimulation of cytokine induction in human \u03b3\u03b4 T cells by TLR8 RNA ligands

Human Vγ9Vδ2 T cells recognize pyrophosphates produced by microbes and transformed cells and play a role in anti-infective immunity and tumor surveillance. Toll-like receptors (TLR) are pattern recognition receptors in innate immune cells which sense microbial structures including nucleic acids. Given that γδ T cells are in clinical development for application in cellular cancer immunotherapy and TLR ligands have potent adjuvant activity, we investigated the co-stimulatory role of selected TLR ligands in γδ T-cell activation. Here we have used recently described RNA ligands for TLR7 and TLR8 together with Vγ9Vδ2 T-cell specific pyrophosphate antigens to analyze the rapid cytokine induction in Vδ2 T cells as well as the accessory cell requirements. While TLR8- as well as TLR7/8-specific RNA did not induce IFN-γ in Vδ2 T cells on their own, they provided strong co-stimulation for Vδ2 T cells within peripheral blood mononuclear cells in the presence of additional T-cell receptor activation. In contrast, TLR7 ligands were ineffective. Purified γδ T cells did not directly respond to TLR8 co-stimulation but required the presence of monocytes. Further experiments revealed a critical role of IL-1β and IL-18, and to a slightly lesser extent of IL-12p70, in the co-stimulation of Vδ2 T cells by TLR8 and TLR7/8 RNA ligands. Results of intracellular cytokine expression were validated by ELISA analysis of cytokines in cell culture supernatants. The cell context-dependent adjuvant activity of TLR8 and TLR7/8 RNA ligands described here might be important for the future optimization of γδ T-cell based cancer immunotherapy.

The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia

Cytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β−/−/CKD, Il6−/−/CKD and Tnfα−/−/CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β−/−/CKD mice but were only partially rescued in Il6−/−/CKD and Tnfα−/−/CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg/kg/day, IP) or saline for 6 weeks and compared with WT/Sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra decreased serum and muscle expression of IL-6, TNF-α and IL-1β in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.

IL11: A Specific Repressor of Tumor-Specific CD4+ T Cells.

CD4+ T helper 1 (Th1) cells have a key role in tumor immunity by producing effector cytokines that orchestrate the tumoricidal effects of cytotoxic T lymphocytes, natural killer cells, and macrophages and directly exert tumor growth control via the induction of tumor cell senescence and inhibition of angiogenesis. In this issue, Huynh and colleagues report a new role for IL11 in fostering tumor outgrowth by suppressing the effector mechanisms of intratumoral CD4+ Th1 cells.See related article by Huynh et al., p. 735.