Interleukin-1 Receptor Family Research Articles

IL1R2 is a Novel Prognostic Biomarker for Lung Adenocarcinoma.

The aim of this study is to figure out the role of IL1R2 in LUAD (lung adenocarcinoma). IL1R2, a special member of IL-1 receptor family, binds to IL-1 and plays an important role in inhibiting IL-1 pathway, which seems to be involved in tumorigenesis. Emerging studies demonstrated higher IL1R2 expression levels in several malignancies. In the present study, we assessed the expression of IL1R2 in LUAD tissues with immunohistochemistry and explored various databases to determine whether it could be a potential prognostic biomarker and therapeutic target. The expression level of IL1R2 in lung adenocarcinoma was analyzed by Immunohistochemistry and UALCAN database. The correlation between IL1R2 expression and the patient prognosis was identified by Kaplan-Meier plotter. The correlation of IL1R2 expression with immune infiltrates was clarified by TIMER database. The protein-protein interaction network and gene functional enrichment analysis were constructed and performed by STRING and Metascape database. Immunohistochemistry showed that the expression of IL1R2 was higher in tumor tissues of LUAD patients and that patients with lower IL1R2 level have a better prognosis than their counterparts. We validated our findings in several online databases and found that IL1R2 gene was also positively correlated with B cells and neutrophils and biomarkers of CD8+T cells and exhausted T cells. PPI network and gene enrichment analyses showed that expression of IL1R2 was also associated with complex functionspecific networks involving IL-1 signal, NF-KappaB transcription factors. According to these findings, we demonstrated that IL1R2 was involved in the progression and prognosis of LUAD and the underlying mechanism needs further investigation.

Association of soluble suppression of tumorigenicity 2 with mortality and adverse outcomes in chronic kidney disease: a systematic review and meta-analysis.

Early risk stratification is necessary to prevent chronic kidney disease progression and complications. This systematic review aims to evaluate the association of soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, with all-cause mortality, cardiovascular disease and renal function deterioration among chronic kidney disease patients. PubMed, Scopus, Web of Science, CENTRAL and Google Scholar were systematically searched from inception to December 20, 2023. Cohort studies examining the prognostic role of sST2 levels in pre-dialysis and dialysis patients were included. In case of 3 or more studies per outcome, conventional and dose-response meta-analyses were conducted. Overall, 21 studies were included comprising 15,100 patients. In pre-dialysis patients, the qualitative synthesis of studies suggested that high sST2 is associated with significantly increased all-cause mortality, while evidence regarding cardiovascular events or kidney disease progression was conflicting. In the dialysis population, high sST2 was linked to an elevated risk of all-cause (Hazard ratio-HR: 3.00, 95% confidence intervals-CI: 1.95-4.61) and cardiovascular (HR: 2.38, 95% CI: 1.69-3.34) mortality. Dose-response meta-analysis suggested a log-linear association of sST2 with both all-cause (χ2: 34.65, p value < 0.001) and cardiovascular (χ2: 29.14, p value < 0.001) mortality, whereas findings regarding cardiovascular events were limited with mixed results. High sST2 values are associated with an increased risk of all-cause mortality in pre-dialysis and dialysis patients, as well as with an elevated risk of cardiovascular mortality in the dialysis population. Further studies are needed to elucidate its potential association with cardiovascular events and kidney disease progression.

Systemic inflammation 72 hours after cardiac arrest is associated with poor neurological outcome and long term all-cause mortality - the prospective Norwegian Cardio-Respiratory Arrest Study (NORCAST)

Abstract Background Post-cardiac arrest (CA) anoxic brain injury seems to involve local and systemic inflammation. The interleukin (IL)-1/IL-6 pathway has gained increased interest both as prognostic markers and as possible targets for intervention. Purpose To evaluate the associations of the IL-1 receptor family, IL-6 and procalcitonin as a marker of systemic inflammation, with neurological outcome and long-term all-cause mortality in patients with out-of-hospital cardiac arrest (OHCA). Methods In this prospective observational study, we included 259 adult patients (&amp;gt; 18 years) hospitalized after OHCA. Blood sampling were performed on admission and 72 hours after cardiac arrest. IL-1 receptor antagonist (IL-1ra), ST2 (soluble interleukin 1 receptor-like 1), IL-6 and procalcitonin were analysed on admission and 72 hours after cardiac arrest. Neurological outcome was measured as cerebral performance category score (CPC score) assessed by two experienced neurologists six months after OHCA. CPC score was dichotomized into good (CPC score 1-2) or poor (CPC score 3-5) neurological outcome. All-cause mortality was registered after median 10.7-year follow-up. Results Patients with poor neurological outcome six months after CA (red bars) had significant higher levels of IL-6 (p = 0.002), IL-1Ra (p &amp;lt; 0.001), ST2 (p &amp;lt; 0.001) and procalcitonin (p &amp;lt; 0.001) 72 hours after CA (Fig. 1). High levels of IL-6, IL-1Ra, ST2 and procalcitonin measured 72 hours after cardiac arrest were significantly associated with long-term all-cause mortality (Fig. 2). Conclusions High levels of inflammatory biomarkers 72 hours after CA were significantly associated with poor neurological outcome and long-term all-cause mortality.Figure 1Figure 2

Soluble suppression of tumorigenicity 2 is a potential predictor of post-liver transplant renal outcomes.

Acute kidney injury is considered an independent prognostic factor for mortality in patients with liver cirrhosis. Non-treated acute kidney injury can progress to hepatorenal syndrome with a poor prognosis. As suppression of tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor family that aggravates inflammation and fibrotic changes in multiple organs, we measured soluble ST2 (sST2) level in the serum and urine of liver-transplant recipients at the time of transplantation. The serum sST2 level significantly increased in liver-transplant recipients with suppressed kidney function compared with that in recipients with normal function. In recipients with severely decreased liver function (model for end-stage liver disease score ≥ 30), the serum sST2 level was higher than that in recipients with preserved liver function (model for end-stage liver disease score ≤ 20, P = 0.028). The serum sST2 level in recipients with hepatorenal syndrome was higher than that in liver-transplant recipients without hepatorenal syndrome (P = 0.003). The serum sST2 level in patients with hepatorenal syndrome was higher than that in recipients without a history of acute kidney injury (P = 0.004). Recipients with hepatorenal syndrome and recovered kidney function showed higher sST2 levels than those who did not recover (P = 0.034). Collectively, an increase in the serum sST2 level reflects a decrease in both kidney and liver functions. Thus, measuring sST2 level at the time of liver transplantation can help predict renal outcomes.

The expression profiling and clinical significance of a chronic pain-related gene IL1R1.

Chronic pain is a disease that existed during cancer treatment for a long time. It has been reported that interleukin (IL)-1 is involved in the inflammatory response during tumor development. IL1R1 and IL1R2 are members of the IL-1 receptor family of cytokine receptors. However, few studies have reported the role of chronic pain-related genes, IL1R1, in pan-cancer. In this study, 8 lumbar disc prolapse (LDP) patients and 8 controls with differentially expressed genes were investigated to find chronic pain-related genes. Then, IL1R1 was analyzed using the TCGA database. The clinical survival data from TCGA were used to analyze the prognostic value of IL1R1. This study further evaluated the relationship between IL1R1 and immune checkpoints, immune-activating genes, immunosuppressive genes, chemokines, and chemokine receptors. IL1R1 was expressed in varying degrees in most TCGA tumor types, indicating a better survival status. The expression of IL1R1 is closely related to T cell infiltration, immune checkpoints, immune-activating genes, immunosuppressive genes, chemokines, and chemokine receptors. The results show that IL1R1 is a kind of potential cancer biomarker. Coordination with other immune checkpoints IL1R1k may adjust the immune microenvironment, immunotherapy can be applied to the development of new targeted drugs.

Soluble ST2 is associated with neurotoxicity following chimeric antigen receptor T-cell therapy (S17.008)

Soluble ST2 is associated with neurotoxicity following chimeric antigen receptor T-cell therapy (S17.008)

Effect of combining sST2/HDL-C ratio with risk factors of coronary heart disease on the detection of angina pectoris in Chinese: a retrospective observational study.

Soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, binds IL-33, preventing its interaction with membrane-bound form ST2 (ST2L), thereby blocking its protection against atherosclerosis. High-density lipoprotein cholesterol (HDL-C), a variety of lipoproteins with mean size of 8-10 nm and density of 1.063-1.21 g/mL, not only acts as lipid transporters that transport cholesterol reversely, but also carries a variety of proteins and microRNAs endowing it with the ability to prevent cardiovascular disease. Most studies on the relationship between sST2 and coronary heart disease (CHD) are limited to acute myocardial infarction (AMI). The present study set out to investigate the association between the sST2/HDL-C ratio and angina pectoris. A retrospective single-center cohort study was conducted and a total of 250 patients with chest pain that formed a convenience series, hospitalized between January 2018 and August 2020, were enrolled. Patients with AMI, acute and chronic heart failure, structural heart disease, renal insufficiency [estimate glomerular filtration rate (eGFR) <60 mL/min/1.73 m2], rheumatic immune diseases, malignant tumors and severe infections were excluded. Patients with missing data were also excluded. Two hundred and nine patients were finally enrolled. Levels of sST2, HDL-C and sST2/HDL-C ratio were measured and calculated after admission. The angina pectoris was diagnosed by combining clinical features, coronary angiography results and cardiac troponin I levels. The diagnosis value of sST2/HDL-C on angina pectoris was analyzed by binary logistic analysis and the receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) assesses. Patients with stable angina pectoris (SAP) or unstable angina pectoris (UAP) accounted for a larger proportion (28.8% vs. 42.9%, P=0.035) in patients with the higher sST2/HDL-C ratio. Binary logistics regression showed that for every unit of sST2/HDL-C increase, the risk of angina pectoris increased by 38.8% (OR =1.388, P=0.018). By subgroup analysis, a stronger association was found in non-diabetic patients (OR =1.551, P=0.006), non-hypertension patients (OR =1.700, P=0.025), non-smokers (OR =1.527, P=0.049) and patients aged <65 y (OR =1.693, P=0.019). ROC curve showed that AUC was higher [0.643 (0.566, 0.719) vs. 0.618 (0.540, 0.696)] and the sensitivity of diagnosis increased significantly (84.0% vs. 49.3%) by combining sST2/HDL-C with risk factors of CHD. A higher ratio of sST2/HDL-C was associated with an increased risk of angina pectoris. sST2/HDL-C combined with CHD risk factors showed increased diagnostic value in identifying angina pectoris. Clinical trial: ChiCTR-DDD-17013908.

Vinculin B inhibits NF-κB signaling pathway by targeting MyD88 in miiuy croaker, Miichthys miiuy

Myeloid differentiation factor 88 (MyD88) is the canonical adaptor for inflammatory signaling pathways downstream from members of the Toll-like receptor (TLR) and interleukin-1 (IL-1) receptor families, which activates the NF-κB signaling pathway and regulates immune and inflammatory responses. In this study, we found that Vinculin B (Vclb) is an inhibitor in the NF-κB signaling pathway, and its inhibitory effect was enhanced by LPS induction. Furthermore, Vclb inhibits NF-κB activation by targeting MyD88, thereby suppressing the production of inflammatory cytokines. Mechanistically, Vclb inhibits the NF-κB signaling pathway by targeting MyD88 ubiquitin-proteasome pathway. In summary, our study reveals that Vclb inhibits NF-κB signaling activation and mediates innate immunity in teleosts via the ubiquitin-proteasome pathway of MyD88.

Transcriptome Analysis of Diffuse Large B-Cell Lymphoma Cells Inducibly Expressing MyD88 L265P Mutation Identifies Upregulated CD44, LGALS3, NFKBIZ, and BATF as Downstream Targets of Oncogenic NF-κB Signaling.

During innate immune responses, myeloid differentiation primary response 88 (MyD88) functions as a critical signaling adaptor protein integrating stimuli from toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family and translates them into specific cellular outcomes. In B cells, somatic mutations in MyD88 trigger oncogenic NF-κB signaling independent of receptor stimulation, which leads to the development of B-cell malignancies. However, the exact molecular mechanisms and downstream signaling targets remain unresolved. We established an inducible system to introduce MyD88 to lymphoma cell lines and performed transcriptomic analysis (RNA-seq) to identify genes differentially expressed by MyD88 bearing the L265P oncogenic mutation. We show that MyD88L265P activates NF-κB signaling and upregulates genes that might contribute to lymphomagenesis, including CD44, LGALS3 (coding Galectin-3), NFKBIZ (coding IkBƺ), and BATF. Moreover, we demonstrate that CD44 can serve as a marker of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and that CD44 expression is correlated with overall survival in DLBCL patients. Our results shed new light on the downstream outcomes of MyD88L265P oncogenic signaling that might be involved in cellular transformation and provide novel therapeutical targets.

PREVALENCE OF POLYMORPHISM OF THE IL1RL1 GENE (rs950880) AMONG RESIDENTS OF THE PODILSK REGION OF UKRAINE

The study of the "genetic architecture" of essential hypertension (EH) is becoming increasingly relevant, in particular, the study of the genetic component of the production of peptides, which are used as biomarkers in cardiology. Soluble ST2 of the interleukin-1 receptor family is a promising marker of myocardial remodeling. The genetic basis of ST2 production - SNP rs950880 of the IL1RL1 gene requires a detailed analysis. The aim of the study was to study the prevalence of SNR rs950880 polymorphic variants of the IL1RL1 gene among men living in the Podilsk region of Ukraine with essential hypertension (EH) of varying severity. Material and methods. In the course of the work, 170 men aged 40 to 60 years were examined: 70 without cardiovascular diseases and 100 patients with EH of varying severity (50 with asymptomatic EH (AEH) and 50 patients with EG complicated by CHF II A stage (EH+CHF)). Determination of polymorphism rs950880 of IL1RL1 gene was performed using polymerase chain reaction (PCR). The statistical analysis of the research results included the calculation of the odds ratio, the analysis of conjugation tables. Results. It was established that among residents of the Podilsk region of Ukraine, the SNP variant rs950880 of the IL1RL1 gene, which has the C allele, is the most common: among men without cardiovascular diseases, carriers of the CC and AC variants dominate (45.72% and 42.86%, respectively), the prevalence is similar SNP rs950880 and among patients with EH of different severity (among patients with EH homozygous CC 42.00%, heterozygous AC - 46.00%; in the group EH+CHF - 38.00% and 48.00%, respectively). The AA variant is the least common in all groups (11.42% in the control group, 12.00% among patients with AEH, 14.00% in the EH+CHF group). Conclusions. According to the frequency distribution of the rs950880 polymorphism of the IL1RL1 gene, men with EH of different severity do not reliably differ from the general population of residents of the Podilsk region. Carriership of the investigated polymorphism is not associated with an increased risk of developing EH or complications of CHF. Variability is observed in the frequency distribution of SNR rs950880 IL1RL1 gene alleles in different populations.

Flow Cytometry Analysis of IL-1 Receptors and Toll-Like Receptors on Platelets and Platelet-Derived Extracellular Vesicles.

Flow cytometry is largely used for the immunophenotyping and quantification of several cell types or related components including platelets and extracellular vesicles. Platelets and platelet-derived extracellular vesicles (PEVs) are receiving increased interest in inflammatory diseases including sepsis. Thus, in this chapter, we will describe protocols for the flow cytometry analysis of platelets, platelet/neutrophils hetero aggregates, and PEVs mainly focusing on the evaluation of the surface expression of some IL-1 receptor (ILR) and Toll-like receptor (TLR) family members.

Soluble suppression of tumorigenicity-2 in pregnancy with a small-for-gestational-age fetus and with preeclampsia

Objective Preeclampsia and fetal growth disorders are pregnancy-specific conditions that share common pathophysiological mechanisms. Yet, why some patients develop preeclampsia while others experience fetal growth restriction, or a combination of both clinical presentations, is unknown. We propose that the difference in severity of the maternal inflammatory response can contribute to the clinical phenotypes of preeclampsia vs. small for gestational age (SGA). To assess this hypothesis, we measured maternal plasma concentrations of the soluble isoform of suppression of tumorigenicity-2 (sST2), a member of the interleukin-1 receptor family that buffers proinflammatory responses. Previous reports showed that serum sST2 concentrations rise in the presence of intravascular inflammation and Th1-type immune responses and are significantly higher in patients with preeclampsia compared to those with normal pregnancy. The behavior of sST2 in pregnancies complicated by SGA has not been reported. This study was conducted to compare sST2 plasma concentrations in normal pregnancies, in those with preeclampsia, and in those with an SGA fetus. Methods This retrospective cross-sectional study included women with an SGA fetus (n = 52), women with preeclampsia (n = 106), and those with normal pregnancy (n = 131). Maternal plasma concentrations of sST2 were determined by enzyme-linked immunosorbent assay. Doppler velocimetry of the uterine and umbilical arteries was available in a subset of patients with SGA (42 patients and 43 patients, respectively). Results (1) Women with an SGA fetus had a significantly higher median plasma concentration of sST2 than normal pregnant women (p = .008); (2) women with preeclampsia had a significantly higher median plasma concentration of sST2 than those with normal pregnancy (p < .001) and those with an SGA fetus (p < .001); (3) patients with SGA and abnormal uterine artery Doppler velocimetry had a higher median plasma concentration of sST2 than controls (p < .01) and those with SGA and normal uterine artery Doppler velocimetry (p = .02); (4) there was no significant difference in the median plasma sST2 concentration between patients with SGA who had normal uterine artery Doppler velocimetry and controls (p = .4); (5) among patients with SGA, those with abnormal and those with normal umbilical artery Doppler velocimetry had higher median plasma sST2 concentrations than controls (p = .001 and p = .02, respectively); and (6) there was no significant difference in the median plasma sST2 concentrations between patients with SGA who did and those who did not have abnormal umbilical artery Doppler velocimetry (p = .06). Conclusions Preeclampsia and disorders of fetal growth are conditions characterized by intravascular inflammation, as reflected by maternal plasma concentrations of sST2. The severity of intravascular inflammation is highest in patients with preeclampsia.

SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is a complex autoimmune disease with multiple etiological factors, among which aberrant memory CD4 T cells activation plays a key role in the initiation and perpetuation of the disease. SIGIRR (single immunoglobulin IL-1R-related receptor), a member of the IL-1 receptor (ILR) family, acts as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation. The aim of this study was to investigate the potential roles of SIGIRR on memory CD4 T cells in RA and the underlying cellular and molecular mechanisms.MethodsSingle-cell transcriptomics and bulk RNA sequencing data were integrated to predict SIGIRR gene distribution on different immune cell types of human PBMCs. Flow cytometry was employed to determine the differential expression of SIGIRR on memory CD4 T cells between the healthy and RA cohorts. A Spearman correlation study was used to determine the relationship between the percentage of SIGIRR+ memory CD4 T cells and RA disease activity. An AIA mouse model (antigen-induced arthritis) and CD4 T cells transfer experiments were performed to investigate the effect of SIGIRR deficiency on the development of arthritis in vivo. Overexpression of SIGIRR in memory CD4 T cells derived from human PBMCs or mouse spleens was utilized to confirm the roles of SIGIRR in the intracellular cytokine production of memory CD4 T cells. Immunoblots and RNA interference were employed to understand the molecular mechanism by which SIGIRR regulates TNF-α production in CD4 T cells.ResultsSIGIRR was preferentially distributed by human memory CD4 T cells, as revealed by single-cell RNA sequencing. SIGIRR expression was substantially reduced in RA patient-derived memory CD4 T cells, which was inversely associated with RA disease activity and related to enhanced TNF-α production. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA), which was attributed to unleashed TNF-α production in memory CD4 T cells, confirmed by decreased TNF-α production resulting from ectopic expression of SIGIRR. Mechanistically, SIGIRR regulates the IL-1/C/EBPβ/TNF-α signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis.ConclusionTaken together, SIGIRR deficiency in memory CD4 T cells in RA raises the possibility that receptor induction can target key abnormalities in T cells and represents a potentially novel strategy for immunomodulatory therapy.

IL-17-induced dimerization of IL-17RA drives the formation of the IL-17 signalosome to potentiate signaling.

Signaling through innate immune receptors such as the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily proceeds via the assembly of large membrane-proximal complexes or "signalosomes." Although structurally distinct, the IL-17 receptor family triggers cellular responses that are typical of innate immune receptors. The IL-17RA receptor subunit is shared by several members of the IL-17 family. Using a combination of crystallographic, biophysical, and mutational studies, we show that IL-17A, IL-17F, and IL-17A/F induce IL-17RA dimerization. X-ray analysis of the heteromeric IL-17A complex with the extracellular domains of the IL-17RA and IL-17RC receptors reveals that cytokine-induced IL-17RA dimerization leads to the formation of a 2:2:2 hexameric signaling assembly. Furthermore, we demonstrate that the formation of the IL-17 signalosome potentiates IL-17-induced IL-36γ and CXCL1 mRNA expression in human keratinocytes, compared with a dimerization-defective IL-17RA variant.

The search for novel biomarkers in sepsis-induced cardiomyopathy – A new challenge to overcome

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and it remains the most frequent cause of death amongst critically ill patients worldwide, despite recent medical advancements. The cardiac involvement in sepsis, better known as sepsis-induced cardiomyopathy, represents a form of cardiac dysfunction identified in septic patients, characterized by ventricular dilation, myocardial involvement, decreased ejection fraction and reversibility. Although the implications of cardiac involvement in sepsis can be extremely severe, this affliction has not been intensely debated in literature. Therefore, in order to better understand this affliction, we need to identify new markers. Two biomarkers, endothelin-1 (ET-1) and the soluble form of suppression of tumorigenicity 2 protein (sST2) have previously been linked to both sepsis and acute/chronic heart failure. Endothelin-1 is part of a family of amino acid peptides, that is mainly produced by endothelial cells and exerts a vasoconstrictive effect, but also causes fibrosis of the vascular cells, stimulates production of reactive oxygen species and induces proinflammatory mechanisms. During sepsis, it induces coronary vasoconstriction, decreased cardiac output, increased vascular resistance and permeability and increased fluid flux into the extravascular space on cardiac level, as well as affecting the contractility of myocardial myocytes. High values of serum ET-1 have also been identified in septic shock and in endotoxin-induced febrile responses in rats. The Suppression of tumorigenicity 2 protein (ST2) is a member of the interleukin-1 receptor family and is involved in T helper 2 cells-associated immune response. Recent studies identified a close link between ST2 and both inflammatory and heart diseases. Furthermore, it was recently approved by the Food and Drug Administration as a prognostic biomarker in heart failure and is recommended for the evaluation of additional cardiovascular risk.

Organizing structural principles of the IL-17 ligand–receptor axis

The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases1. The compositions and structures of functional IL-17 family ligand–receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses2. Here we studied IL-25–IL-17RB binary and IL-25–IL-17RB–IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25–IL-17RB–IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25–IL-17RB homodimer is flanked by two ‘wing-like’ IL-17RA co-receptors through a ‘tip-to-tip’ geometry that is the key receptor–receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB–IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A–IL-17RA and IL-17A–IL-17RA–IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor.

Negative Regulation of the IL-1 System by IL-1R2 and IL-1R8: Relevance in Pathophysiology and Disease.

Interleukin-1 (IL-1) is a primary cytokine of innate immunity and inflammation. IL-1 belongs to a complex family including ligands with agonist activity, receptor antagonists, and an anti-inflammatory cytokine. The receptors for these ligands, the IL-1 Receptor (IL-1R) family, include signaling receptor complexes, decoy receptors, and negative regulators. Agonists and regulatory molecules co-evolved, suggesting the evolutionary relevance of a tight control of inflammatory responses, which ensures a balance between amplification of innate immunity and uncontrolled inflammation. IL-1 family members interact with innate immunity cells promoting innate immunity, as well as with innate and adaptive lymphoid cells, contributing to their differentiation and functional polarization and plasticity. Here we will review the properties of two key regulatory receptors of the IL-1 system, IL-1R2, the first decoy receptor identified, and IL-1R8, a pleiotropic regulator of different IL-1 family members and co-receptor for IL-37, the anti-inflammatory member of the IL-1 family. Their complex impact in pathology, ranging from infections and inflammatory responses, to cancer and neurologic disorders, as well as clinical implications and potential therapeutic exploitation will be presented.

Assessment of soluble ST2 as a novel cardiac biomarker in cats with cardiomyopathy

Soluble suppression of tumorigenesis-2 (sST2), a member of the interleukin-1 receptor family, is a novel biomarker of mechanical stress that is measurable in serum. It has been shown in humans and animals to be physiologically related to cardiac hypertrophy, fibrosis, and ventricular dysfunction. This study aimed to evaluate sST2 levels in cats with cardiomyopathy. In addition, serum sST2 and other cardiac biomarker levels were compared. Twenty-four client-owned cats with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) were investigated. The cats included in the study were divided into four groups (I, II, III, and IV) according to the American College of Veterinary Internal Medicine (ACVIM) classification. Class B1 cats were included in group I (n=7), class B2 cats were included in group II (n=6), class C cats were included in group III (n=6), and healthy control-group cats in group IV (n=5). Measurement of cardiac troponin I (cTnI), cardiac troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase-MB (CK-MB), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), sST2 levels, and echocardiographic examinations were performed in all groups, and correlations were investigated. We observed positive correlations among sST2 levels and CK-MB and LA diameter (p=0.05). There was no correlation between sST2, NT-proBNP, Troponin I, Troponin T, AST, and LDH levels. We confirmed positive correlations between NT-proBNP levels and LA diameter (p&lt;0.05), CK-MB, IVSd, LVFWd, and LA/Ao ratio (p&lt;0.01). Cardiac biomarkers have diagnostic significance for feline cardiomyopathies. There was no statistically significant difference in sST2 levels between the groups. However, further research is needed to investigate the relationship between the severity of cardiomyopathies and sST2 levels in cats.

Soluble suppression of tumorigenicity 2 (sST2) for predicting disease severity or mortality outcomes in cardiovascular diseases: A systematic review and meta-analysis

ObjectivesSoluble suppression of tumorigenicity 2 (sST2) is a member of the interleukin-1 receptor family. It is raised in various cardiovascular diseases, but its value in predicting disease severity or mortality outcomes has been controversial. Therefore, we conducted a systematic review and meta-analysis to determine whether sST2 levels differed between survivors and non-survivors of patients with cardiovascular diseases, and whether elevated sST2 levels correlated with adverse outcomes.MethodsPubMed and Embase were searched until 23rd June 2021 for studies that evaluated the relationship between sST2 levels and cardiovascular disease severity or mortality.ResultsA total of 707 entries were retrieved from both databases, of which 14 studies were included in the final meta-analysis. In acute heart failure, sST2 levels did not differ between survivors and non-survivors (mean difference [MD]: 24.2 ± 13.0 ng/ml; P = 0.06; I2: 95%). Elevated sST2 levels tend to be associated with increased mortality risk (hazard ratio [HR]: 1.12, 95 %CI: 0.99–1.27, P = 0.07; I2: 88%). In chronic heart failure, sST2 levels were higher in non-survivors than in survivors (MD: 0.19 ± 0.04 ng/ml; P = 0.001; I2: 0%) and elevated levels were associated with increased mortality risk (HR: 1.64, 95% CI: 1.27–2.12, P < 0.001; I2: 82%). sST2 levels were significantly higher in severe disease compared to less severe disease (MD: 1.56 ± 0.46 ng/ml; P = 0.001; I2: 98%). Finally, in stable coronary artery disease, sST2 levels were higher in non-survivors than survivors (MD: 3.0 ± 1.1 ng/ml; P = 0.005; I2: 80%) and elevated levels were significantly associated with increased mortality risk (HR: 1.32, 95% CI: 1.04–1.68, P < 0.05; I2: 57%).ConclusionssST2 significantly predicts disease severity and mortality in cardiovascular disease and is a good predictor of mortality in patients with stable coronary artery disease and chronic heart failure.

Rational Design, Synthesis and Evaluation of Oxazolo[4,5-c]-quinolinone Analogs as Novel Interleukin-33 Inhibitors.

Interleukin-33 (IL-33) is an epithelial-derived cytokine that plays an important role in immune-mediated diseases such as asthma, atopic dermatitis, and rheumatoid arthritis. Although IL-33 is considered a potential target for the treatment of allergy-related diseases, no small molecule that inhibits IL-33 has been reported. Based on the structure-activity relationship and in vitro 2D NMR studies employing 15 N-labeled IL-33, we identified that the oxazolo[4,5-c]-quinolinone analog 7 c binds to the interface region of IL-33 and IL-33 receptor (ST2), an orphan receptor of the IL-1 receptor family. Compound 7 c effectively inhibited the production of IL-6 in human mast cells in a dose-dependent manner. Compound 7 c is the first low molecular weight IL-33 inhibitor and may be used as a prototype molecule for structural optimization and investigation of the IL-33/ST2 signaling pathway.