Interleukin 1 Receptor-like 1 Research Articles

Amniotic fluid proteomic analysis identifies IL1RL1, APOE, and NECTIN4 as new biomarkers for preterm birth

BackgroundDespite extensive research, the identification of effective biomarkers for early prediction of preterm birth (PTB) continues to be a challenging endeavor. This study aims to identify amniotic fluid (AF) protein biomarkers useful for the early diagnosis of PTB.MethodsWe initially identified the protein expression profiles in the AF of women with PTB (n = 22) and full-term birth (FTB, n = 22), from the First People’s Hospital of Yunnan Province who underwent amniocentesis from November 2019 to February 2020, using mass spectrometry employing the data-independent acquisition (DIA) technique, and then analyzed differentially expressed proteins (DEPs). Subsequently, the least absolute shrinkage and selection operator (LASSO) and random forest analysis were employed to further screen the key proteins for PTB biomarker identification. The receiver operating characteristic (ROC) analysis, calibration plots, and decision curve analyses (DCA) were utilized to assess the discrimination and calibration of the key biomarkers.ResultsA total of 25 DEPs were identified between the PTB and FTB groups, comprising 13 up-regulated and 12 down-regulated proteins. Three key protein biomarkers for early PTB diagnosis were identified: IL1RL1 (interleukin-1 receptor-like 1), APOE (apolipoprotein E), and NECTIN4 (nectin cell adhesion molecule 4). The results of the ROC analysis showed that the area under the curve (AUC) of the three proteins combined as a biomarker for early diagnosis of PTB was 0.913 (95% CI: 0.823-1.000), with a sensitivity of 0.864 and a specificity of 0.955, both superior to those of the individual biomarkers. Bootstrap internal validation revealed a concordance index (C-index) of 0.878, with a sensitivity of 0.812 and a specificity of 0.773, indicating the robust predictive performance of these biomarkers.ConclusionsWe identified three previously unexplored yet potentially useful protein biomarkers in AF for early PTB diagnosis: IL1RL1, APOE, and NECTIN4.

The Diagnostic Accuracy of N-Terminal Pro-B-Type Natriuretic Peptide and Soluble ST2 for Heart Failure in Chronic Kidney Disease Patients: A Comparative Analysis.

BACKGROUND N-terminal proatrial natriuretic peptide (NT-proBNP) levels are often markedly elevated in patients with chronic kidney disease (CKD). Identifying novel biomarkers is an important step toward effective diagnosis. Interleukin-1 receptor-like 1 (IL1RL1) protein and human/Soluble suppression of tumorigenesis-2 (sST2) are promising biomarkers for heart failure (HF). This study aimed to assess the trend of NT-proBNP and sST2 in chronic kidney disease and their diagnostic value for HF. MATERIAL AND METHODS This study was carried out on 420 patients who were divided into a no heart failure group (N=182) and a heart failure group (N=238). Spearman correlation analysis was used to test the association of sST2 and NT-proBNP with renal function. The diagnostic value of each biomarker was assessed using receiver operating characteristic (ROC) curves according to 3 different forms: Total group (n=420), non-CKD group (n=217), and CKD group (n=203). RESULTS A striking correlation between eGFR and NT-proBNP (r=-0.525; P<0.001) seemed to be far stronger than that with sST2 (r=-0.147; P<0.05). The optimum cutoff points for sST2 and NT-proBNP to detect HF were 28.960 ng/mL and 1280 pg/mL, respectively, in total, 28.71 ng/mL and 481 pg/mL, respectively, in non-CKD patients, and 30.55 ng/mL and 3314 pg/mL, respectively, in CKD patients. The combined model of sST2 and NT-proBNP was superior to the model of sST2 or NT-proBNP alone, and the difference was statistically significant (P<0.05). CONCLUSIONS The diagnostic value of sST2 is less affected by decreased renal function. sST2 combined with NT-proBNP may improve the diagnostic accuracy of HF.

Long term exposure of cigarette smoke condensate (CSC) mediates transcriptomic changes in normal human lung epithelial Beas-2b cells and protection by garlic compounds.

Chronic cigarette smoke condensate (CSC) exposure is one of the preventable risk factors in the CS-induced lung cancer. However, understanding the mechanism of cellular transformation induced by CS in the lung remains limited. We investigated the effect of long term exposure of CSC in human normal lung epithelial Beas-2b cells, and chemopreventive mechanism of organosulphur garlic compounds, diallyl sulphide (DAS) and diallyl disulphide (DADS) using Next Generation Sequencing (NGS) transcriptomic analysis. CSC regulated 1077 genes and of these 36 genes are modulated by DAS while 101 genes by DADS. DAS modulated genes like IL1RL1 (interleukin-1 receptor like-1), HSPA-6 (heat shock protein family A, member 6) while DADS demonstrating ADTRP (Androgen-Dependent TFPI Regulating Protein), ANGPT4 (Angiopoietin 4), GFI1 (Growth Factor-Independent 1 Transcriptional Repressor), TBX2 (T-Box Transcription Factor 2), with some common genes like NEURL-1 (Neuralized E3-Ubiquitin Protein Ligase 1), suggesting differential effects between these two garlic compounds. They regulate genes by influencing pathways including HIF-1alpha, STAT-3 and matrix metalloproteases, contributing to the chemoprotective ability of organosulfur garlic compounds against CSC-induced cellular transformation. Taken together, we demonstrated CSC induced global gene expression changes pertaining to cellular transformation which potentially can be delayed with dietary chemopreventive phytochemicals like DS and DADS influencing alterations at the transcriptomic level.

Single nucleotide variants in the IL33 and IL1RL1 (ST2) genes are associated with periodontitis and with Aggregatibacter actinomycetemcomitans in the dental plaque biofilm: A putative role in understanding the host immune response in periodontitis.

The Interleukin (IL)-33 is important in several inflammatory diseases and its cellular receptor is the Interleukin 1 receptor-like 1 (IL1RL1), also called suppression of tumorigenicity 2 ligand (ST2L). This study investigated associations between single nucleotide variants (SNVs) in the IL33 gene and in the IL1RL1 (ST2) gene with periodontitis. Additionally, aimed to determine the role of Aggregatibacter actinomycetemcomitans (Aa) relative amount in the subgingival biofilm in these associations. A cross-sectional study was carried out with 506 individuals that answered a structured questionnaire used to collect their health status, socioeconomic-demographic, and behavioral characteristics. Periodontal examination was performed to determine the presence and severity of periodontitis, and subgingival biofilm samples were collected to quantify the relative amount of Aa by real time polymerase chain reaction. Human genomic DNA was extracted from whole blood cells and SNV genotyping was performed. Logistic regression estimated the association measurements, odds ratio (OR), and 95% confidence interval (95%CI), between the IL33 and ST2 genes with periodontitis, and subgroup analyses assessed the relative amount of Aa in these associations. 23% of individuals had periodontitis. Adjusted measurements showed a statistically significant inverse association between two SNVs of the ST2; rs148548829 (C allele) and rs10206753 (G allele). These two alleles together with a third SNV, the rs11693204 (A allele), were inversely associated with moderate periodontitis. One SNV of the IL33 gene also showed a statistically significant inverse association with moderate periodontitis. Nine SNVs of the ST2 gene were inversely associated with the relative amount of Aa. In the high Aa subgroup, there was a direct association between 11 SNVs of the ST2 gene and moderate periodontitis and two SNVs of the ST2 gene and severe periodontitis, and eight SNVs of the ST2 gene and periodontitis. These exploratory findings of genetic variants in IL-33/ST2 axis support the concept that the different tissue responses among individuals with periodontitis may be modulated by the host's genetics, influencing the physiopathology of the disease.

The Differentially Expressed Genes Responsible for the Development of T Helper 9 Cells From T Helper 2 Cells in Various Disease States: Immuno-Interactomics Study

Background T helper (Th) 9 cells are a novel subset of Th cells that develop independently from Th2 cells and are characterized by the secretion of interleukin (IL)-9. Studies have suggested the involvement of Th9 cells in variable diseases such as allergic and pulmonary diseases (eg, asthma, chronic obstructive airway disease, chronic rhinosinusitis, nasal polyps, and pulmonary hypoplasia), metabolic diseases (eg, acute leukemia, myelocytic leukemia, breast cancer, lung cancer, melanoma, pancreatic cancer), neuropsychiatric disorders (eg, Alzheimer disease), autoimmune diseases (eg, Graves disease, Crohn disease, colitis, psoriasis, systemic lupus erythematosus, systemic scleroderma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atopic dermatitis, eczema), and infectious diseases (eg, tuberculosis, hepatitis). However, there is a dearth of information on its involvement in other metabolic, neuropsychiatric, and infectious diseases. Objective This study aims to identify significant differentially altered genes in the conversion of Th2 to Th9 cells, and their regulating microRNAs (miRs) from publicly available Gene Expression Omnibus data sets of the mouse model using in silico analysis to unravel various pathogenic pathways involved in disease processes. Methods Using differentially expressed genes (DEGs) identified from 2 publicly available data sets (GSE99166 and GSE123501) we performed functional enrichment and network analyses to identify pathways, protein-protein interactions, miR-messenger RNA associations, and disease-gene associations related to significant differentially altered genes implicated in the conversion of Th2 to Th9 cells. Results We extracted 260 common downregulated, 236 common upregulated, and 634 common DEGs from the expression profiles of data sets GSE99166 and GSE123501. Codifferentially expressed ILs, cytokines, receptors, and transcription factors (TFs) were enriched in 7 crucial Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology. We constructed the protein-protein interaction network and predicted the top regulatory miRs involved in the Th2 to Th9 differentiation pathways. We also identified various metabolic, allergic and pulmonary, neuropsychiatric, autoimmune, and infectious diseases as well as carcinomas where the differentiation of Th2 to Th9 may play a crucial role. Conclusions This study identified hitherto unexplored possible associations between Th9 and disease states. Some important ILs, including CCL1 (chemokine [C-C motif] ligand 1), CCL20 (chemokine [C-C motif] ligand 20), IL-13, IL-4, IL-12A, and IL-9; receptors, including IL-12RB1, IL-4RA (interleukin 9 receptor alpha), CD53 (cluster of differentiation 53), CD6 (cluster of differentiation 6), CD5 (cluster of differentiation 5), CD83 (cluster of differentiation 83), CD197 (cluster of differentiation 197), IL-1RL1 (interleukin 1 receptor-like 1), CD101 (cluster of differentiation 101), CD96 (cluster of differentiation 96), CD72 (cluster of differentiation 72), CD7 (cluster of differentiation 7), CD152 (cytotoxic T lymphocyte–associated protein 4), CD38 (cluster of differentiation 38), CX3CR1 (chemokine [C-X3-C motif] receptor 1), CTLA2A (cytotoxic T lymphocyte–associated protein 2 alpha), CTLA28, and CD196 (cluster of differentiation 196); and TFs, including FOXP3 (forkhead box P3), IRF8 (interferon regulatory factor 8), FOXP2 (forkhead box P2), RORA (RAR-related orphan receptor alpha), AHR (aryl-hydrocarbon receptor), MAF (avian musculoaponeurotic fibrosarcoma oncogene homolog), SMAD6 (SMAD family member 6), JUN (Jun proto-oncogene), JAK2 (Janus kinase 2), EP300 (E1A binding protein p300), ATF6 (activating transcription factor 6), BTAF1 (B-TFIID TATA-box binding protein associated factor 1), BAFT (basic leucine zipper transcription factor), NOTCH1 (neurogenic locus notch homolog protein 1), GATA3 (GATA binding protein 3), SATB1 (special AT-rich sequence binding protein 1), BMP7 (bone morphogenetic protein 7), and PPARG (peroxisome proliferator–activated receptor gamma, were able to identify significant differentially altered genes in the conversion of Th2 to Th9 cells. We identified some common miRs that could target the DEGs. The scarcity of studies on the role of Th9 in metabolic diseases highlights the lacunae in this field. Our study provides the rationale for exploring the role of Th9 in various metabolic disorders such as diabetes mellitus, diabetic nephropathy, hypertensive disease, ischemic stroke, steatohepatitis, liver fibrosis, obesity, adenocarcinoma, glioblastoma and glioma, malignant neoplasm of stomach, melanoma, neuroblastoma, osteosarcoma, pancreatic carcinoma, prostate carcinoma, and stomach carcinoma.

Novel Chemical Series of Anti-ST2 Small Molecules Suppress Allogeneic T Cells Proliferation While Increasing Treg Cells and Improve Gvhd and Survival In Vivo

Elevation of soluble Stimulation-2 (sST2) is considered a prognostic biomarker in several disease progression, such as cardiac allo-rejection, graft-versus-host disease (GVHD), and is associated with the response to tissue damage that secrets Interleukin-33 (IL-33), an alarmin. sST2 is an alternatively spliced isoform of the Interleukin 1 Receptor-Like 1 (IL1RL1) gene that also encodes the major membrane-bound ST2 (ST2) isoform expressed on tolerogenic immune cells including Foxp3+ regulatory T cells (Tregs), type 2 innate lymphoid cells (ILC2), type 2 helper T cells (Th2), monocytes, M2 macrophages, mast cells, eosinophils and neutrophils. IL-33 is the only known ligand that binds to both sST2 and ST2. Binding of IL-33 to ST2 activates intracellular signaling in ST2 expressing cells whereas sST2 functions as a decoy receptor to sequester the secreted free IL-33. After allogeneic hematopoietic cell transplantation (HCT), elevated sST2 levels are associated with patients with GVHD resistant to steroid therapy and with subsequent non-relapse related death. We hypothesized that therapeutic intervention to release IL-33 from sST2 may modulate the T cells responses for treating GVHD. As proof-of-concept, we have reported studies using either ST2 antibodies (Zhang et. al., Sci. Trans. Med. 2015) or small-molecule ST2 inhibitors (iST2-1 in Ramadan et. al., JCI Insight, 2018) in the murine GVHD models. Herein, we report a novel series of small-molecule ST2 inhibitors from our follow-up development of iST2-1. We show a representative compound, XY-52, effectively reduced sST2 levels, alleviated GVHD and improved survival in a murine GVHD model. Based on our previously discovered iST2-1, we recently developed 1-(furan-2ylmethyl)pyrrolidine-based ST2 Inhibitors and constructed the structure-activity relationship (SAR) of compounds against ST2/IL-33 binding (Yuan et. al., Bioorg. Med. Chem., 2022). That study led to identify 14e (Fig. 1A) that has an IC50 value of 7.77 mM against ST2/IL33 binding determined by the AlphaLISA assay. Despite the improvement of the IC50 value as compared to iST2-1, 14e has deficiency in solubility and metabolic stability (including a similar in vivo half-life as iST2-1) that required further optimization. To improve 14e, we first focused on replacing the furan group (C-ring) of 14e with the goal of eliminating the potential metabolic issue of the furan group. We found replacement of furan by either a pyrrole (ST2-J-100) or an alkylated pyrrole group (ST2-J-106, 107) retained the activity of the inhibitors. We then investigated the replacement of the chemical groups on A and B rings of 14e aiming to improve the solubility of the inhibitors while maintaining their activities. These modifications led to identify a new series of ST2 inhibitors represented by XY-52. In the mixed lymphocyte reaction (MLR) assay, we found XY-52 and analogs (XY-125, XY-146, XY-148, XY-150) inhibited CD4+, CD8+ T cell proliferation while increased Tregs (Fig. 1B). XY-52 has improved in vitro (t1/2= >60m in mouse, 41m in human liver microsome) and in vivo metabolic stability. In vivo PK study showed that XY-52 has higher tissue distribution including spleen, lung, skin, small intestine and liver than iST2-1 or Ruxolitinib (Fig. 1C). XY-52 was then selected to compare with 3c (previously reported) in a clinically relevant minor-mismatched GVHD mouse model (C57BL/6→C3H.SW). Using a 21-day prophylactic regimen of 40mg/kg/day (BID), we found that 3c reduced GVHD score (P=0.02) and extended survival (HR 3.90, P=0.02) in mice. Mice receiving XY-52 treatment had a more profound reduction in GVHD score (P<0.0001) and improvement in survival (HR, 31.22, P<0.0001) (Fig. 1D). Both 3c and XY-52 yielded lower plasma concentrations of sST2 and IFNg compared with the DMSO control (Fig. 1E) at Day 7 and 21 post-HCT. Ex vivo analysis of T cells in the gastrointestinal tract (GI) at day 21 post-HCT showed that XY-52 was more effective than 3c at reducing CD4+ IFNg+, CD8+ IFNγ+, CD4+ IL-17A+ T cells and increasing CD4+ Foxp3+ Tregs frequencies. In summary, XY-52 represents a promising ST2 inhibitor that reduces the plasma sST2 levels, CD4+, CD8+ effector T cells and increases CD4+ Foxp3+ Tregs frequencies in in vitro and in vivo GVHD models. Further improvement in the potency and the PK profile of XY-52 will allow us to develop effective ST2 inhibitors for use as a prophylactic or therapeutic regimen for GVHD therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IL1RL1 single nucleotide polymorphisms are associated with asthma in the Iranian population

Asthma is a chronic and multifactorial disease which is known to result from environmental and genetic factors. Interleukin 1 receptor-like 1 (IL1RL1) is a receptor, which promotes inflammatory responses after binding to its ligand IL-33. Several studies have shown that IL1RL1 gene polymorphisms are related to susceptibility or protection to asthma. The objective of this study was to evaluate the association between two IL1RL1 single nucleotide polymorphisms (rs10208293 and rs1041973) and the risk of asthma in the Iranian population. We performed genotyping of the IL1RL1 SNPs in 126 adult asthmatics and 300 healthy controls using TaqMan genotyping assay. Moreover, total serum IgE level, eosinophil count, and skin prick test were accomplished. The results indicated that the AA genotype of rs10208293 was positively associated with asthma susceptibility (p=0.028). We did not find any association between rs1041973 and asthma. Overall, our findings indicate that rs10208293 has a positive association with asthma in the Iranian population.

Association of IL33, IL1RL1, IL1RAP Polymorphisms and Asthma in Chinese Han Children.

Background: Genome-wide association studies have identified interleukin 33 (IL33), interleukin 1 receptor-like 1 (IL1RL1), interleukin 1 receptor accessory protein (IL1RAP) as asthma susceptibility loci in Europeans. IL33, IL1RL1, and IL1RAP constitute a ligand-receptor complex. Objective: We analyzed associations of asthma susceptibility, eosinophilic airway inflammation, and response to inhaled corticosteroid (ICS) with single nucleotide polymorphisms (SNPs) of 3 genes encoding IL33, IL1RL1, and its coreceptor IL1RAP in Chinese Han nationality children. Methods: A total of 153 non-asthmatic children and 265 asthmatic children who visited the Xiangya Hospital between September 2015 and August 2019 were recruited for this study. Pulmonary function tests, peripheral blood eosinophil counts (PBEC), and fractional exhaled nitric oxide (FeNO) tests were performed before treatment, and 3 months after treatment. Each participant’s DNA was extracted from the peripheral blood, and a Mass ARRAY system was used to genotype the SNPs. Results: The T allele of rs4742170 in IL33 was associated with a risk of higher FeNO at baseline, and no improvement in FeNO and airway hyperresponsiveness was found after ICS treatment. The A allele of rs10208293 and C allele of rs13424006 in IL1RL1 both were associated with lower susceptibility to asthma and lower FeNO. The TT genotype of rs1420101 and AA genotype of rs4142132 in IL1RL1 were associated with a greater probability of improvement in PBEC after ICS treatment. Conclusion: IL33-IL1RL1-IL1RAP complex polymorphisms are associated with childhood asthma susceptibility, eosinophilic airway inflammation, and ICS response in Chinese Han children in Hunan. We speculate that IL33-IL1RL1-IL1RAP complex polymorphisms affect the development of asthma, airway inflammation, and subsequent ICS response in childhood.

Altered mRNA Expression of Interleukin-1 Receptors in Myocardial Tissue of Patients with Left Ventricular Assist Device Support.

Serum levels of cytokines interleukin 1 beta ( IL-1β) and interleukin 33 (IL-33) are highly abnormal in heart failure and remain elevated after mechanical circulatory support (MCS). However, local cytokine signaling induction remains elusive. Left (LV) and right ventricular (RV) myocardial tissue specimens of end-stage heart failure (HF) patients without (n = 24) and with MCS (n = 39; 594 ± 57 days) were analyzed for cytokine mRNA expression level of IL-1B, interleukin 1 receptor 1/2 (IL-1R1/2), interleukin 1 receptor-like 1 (IL-1RL1), IL-33 and interleukin-1 receptor accessory protein (IL-1RaP). MCS patients showed significantly elevated IL-1B expression levels (LV: 2.0 fold, p = 0.0058; RV: 3.3 fold, p < 0.0001). Moreover, IL-1R1, IL-1RaP and IL-33 expression levels strongly correlated with each other. IL-1RL1 and IL-1R2 expression levels were significantly higher in RV myocardial tissue (RV/LV ratio IL-1R2 HF: 4.400 ± 1.359; MCS: 4.657 ± 0.655; IL-1RL1 HF: 3.697 ± 0.876; MCS: 4.529 ± 0.5839). In addition, IL1-RaP and IL-33 RV expression levels were significantly elevated in MCS. Furthermore, IL-33 expression correlates with C-reactive protein (CRP) plasma levels in HF, but not in MCS patients. Increased expression of IL-1B and altered correlation patterns of IL-1 receptors indicate enhanced IL-1β signaling in MCS patients. Correlation of IL-1 receptor expression with IL-33 may hint towards a link between both pathways. Moreover, diverging expression in LV and RV suggests specific regulation of local cytokine signaling.

Interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection

The Toll-interleukin 1 receptor superfamily includes the genes interleukin 1 receptor-like 1 (IL1RL1), Toll like receptors (TLRs), myeloid differentiation primary-response 88 (MyD88), and MyD88 adaptor-like (TIRAP). This study describes the interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection. Cases and controls were genotyped at the polymorphic sites MyD88 rs6853, TIRAP rs8177374 and IL1RL1 rs11123923. The results show that specific combinations of IL1RL1-TIRAP (AA-CT; P: 2,8 × 10–17) and MyD88-TIRAP-IL1RL1 (AA-CT-AA; P: 1,4 × 10–8) – but not MyD88 alone—act synergistically against Helicobacter pylori. Nuclear magnetic resonance (NMR) clearly discriminates cases from controls by highlighting significantly different expression levels of several metabolites (tyrosine, tryptophan, phenylalanine, branched-chain amino acids, short chain fatty acids, glucose, sucrose, urea, etc.). NMR also identifies the following dysregulated metabolic pathways associated to Helicobacter pylori infection: phenylalanine and tyrosine metabolism, pterine biosynthesis, starch and sucrose metabolism, and galactose metabolism. Furthermore, NMR discriminates between the cases heterozygous at the IL1RL1 locus from those homozygous at the same locus. Heterozygous patients are characterized by high levels of lactate, and IL1RL1—both associated with anti-inflammatory activity—and low levels of the pro-inflammatory molecules IL-1β, TNF-α, COX-2, and IL-6.

Biotoxic effects and gene expression regulation of urban PM2.5 in southwestern China

Atmospheric fine particulate matter (PM2.5) causes severe haze in China and is regarded as a threat to human health. The health effects of PM2.5 vary location by location due to the variation in size distribution, chemical composition, and sources. In this study, the cytotoxicity effect, oxidative stress, and gene expression regulation of PM2.5 in Chengdu and Chongqing, two typical urban areas in southern China, were evaluated. Urban PM2.5 in summer and winter significantly inhibited cell viability and increased reactive oxygen species (ROS) levels in A549 cells. Notably, PM2.5 in winter exhibited higher cytotoxicity and ROS level than summer. Moreover, in this study, PM2.5 commonly induced cancer-related gene expression such as cell adhesion molecule 1 (PECAM1), interleukin 24 (IL24), and cytochrome P450 (CYP1A1); meanwhile, PM2.5 commonly acted on cancer-related biological functions such as cell-substrate junction, cell-cell junction, and focal adhesion. In particular, PM2.5 in Chengdu in summer had the highest carcinogenic potential among PM2.5 at the two sites in summer and winter. Importantly, cancer-related genes were uniquely targeted by PM2.5, such as epithelial splicing regulatory protein 1 (ESRP1) and membrane-associated ring-CH-type finger 1 (1-Mar) by Chengdu summer PM2.5; collagen type IX alpha 3 chain (COL9A3) by Chengdu winter PM2.5; SH2 domain-containing 1B (SH2D1B) by Chongqing summer PM2.5; and interleukin 1 receptor-like 1 (IL1RL1) and zinc finger protein 42 (ZNF423) by Chongqing winter PM2.5. Meanwhile, important cancer-related biological functions were specially induced by PM2.5, such as cell cycle checkpoint by Chengdu summer PM2.5; macromolecule methylation by Chengdu winter PM2.5; endoplasmic reticulum-Golgi intermediate compartment membrane by Chongqing summer PM2.5; and cellular lipid catabolic process by Chongqing winter PM2.5. Conclusively, in the typical urban areas of southern China, both summer and winter PM2.5 illustrated significant gene regulation effects. This study contributes to evaluating the adverse health effects of PM2.5 in southern China and providing public health suggestions for policymakers.

ST2 Signaling in the Tumor Microenvironment.

Suppression of tumorigenicity 2 (ST2), also known as interleukin-1 receptor-like 1 (IL1RL1), is one of the natural receptors of IL-33. Three major isoforms, ST2L (transmembrane form), sST2 (soluble form), and ST2V, are generated by alternative splicing. Damage to stromal cells induces necrosis and release of IL-33, which binds to heterodimeric ST2L/IL-1RAcP complex on the membrane of a variety of immune cells. This IL-33/ST2L signal induces transcription of the downstream inflammatory and anti-inflammatory genes by activating diverse intracellular kinases and factors to mount an adequate immune response, even in tumor microenvironment. For example, activation of IL-33/ST2L signal may trigger Th2-dependent M2 macrophage polarization to facilitate tumor progression. Notably, sST2 is a soluble form of ST2 that lacks a transmembrane domain but preserves an extracellular domain similar to ST2L, which acts as a "decoy" receptor for IL-33. sST2 has been shown to involve in the inflammatory tumor microenvironment and the progression of colorectal cancer, non-small cell lung cancer, and gastric cancer. Therefore, targeting the IL-33/ST2 axis becomes a promising new immunotherapy for treatment of many cancers. This chapter reviews the recent findings on IL-33/ST2L signaling in tumor microenvironment, the trafficking mode of sST2, and the pharmacological strategies to target IL-33/ST2 axis for cancer treatment.

Interleukin 1 Receptor-Like 1 (IL1RL1) Promotes Airway Bacterial and Viral Infection and Inflammation.

Interleukin 1 receptor-like 1 (IL1RL1), also known as suppression of tumorigenicity 2 (ST2), is the receptor for interleukin 33 (IL-33) and has been increasingly studied in type 2 inflammation. An increase in airway IL-33/ST2 signaling in asthma has been associated with eosinophilic inflammation, but little is known about the role of ST2 in neutrophilic inflammation. Airway Mycoplasma pneumoniae and human rhinovirus (HRV) infections are linked to neutrophilic inflammation during acute exacerbations of asthma. However, whether ST2 contributes to M. pneumoniae- and HRV-mediated airway inflammation is poorly understood. The current study sought to determine the functions of ST2 during airway M. pneumoniae or HRV infection. In cultured normal human primary airway epithelial cells, ST2 overexpression (OE) increased the production of neutrophilic chemoattractant IL-8 in the absence or presence of M. pneumoniae or HRV1B infection. ST2 OE also enhanced HRV1B-induced IP-10, a chemokine involved in asthma exacerbations. In the M. pneumoniae-infected mouse model, ST2 deficiency, in contrast to sufficiency, significantly reduced the levels of neutrophils following acute (≤24 h) infection, while in the HRV1B-infected mouse model, ST2 deficiency significantly reduced the levels of proinflammatory cytokines KC, IP-10, and IL-33 in bronchoalveolar lavage (BAL) fluid. Overall, ST2 overexpression in human epithelial cells and ST2 sufficiency in mice increased the M. pneumoniae and HRV loads in cell supernatants and BAL fluid. After pathogen infection, ST2-deficient mice showed a higher level of the host defense protein lactotransferrin in BAL fluid. Our data suggest that ST2 promotes proinflammatory responses (e.g., neutrophils) to airway bacterial and viral infection and that blocking ST2 signaling may broadly attenuate airway infection and inflammation.

Increased Left Ventricular mRNA Levels of the Inflammatory Biomarkers Pentraxin‐3 and Interleukin 1 Receptor‐Like 1 are Correlated with Diastolic Dysfunction in a Pre‐Clinical Swine Model of HFpEF

Approximately 50% of heart failure cases are diagnosed as heart failure with preserved ejection fraction (HFpEF). HFpEF is challenging to accurately diagnose given traditional biomarkers, such as natriuretic peptide levels, have shown reduced prognostic value for HFpEF patients. Thus, the purpose of this study was to identify biomarkers considered potentially relevant to HFpEF in a new pre‐clinical Ossabaw swine model of heart failure. We hypothesized female Ossabaw swine fed a Western Diet and subject to chronic cardiac pressure‐overload would display physiologic features and biomarkers relevant to HFpEF. Animals were assigned into control (CON, n=5) and Western Diet‐fed aortic‐banded heart failure (WD‐AB, n=4) groups. WD‐AB animals were fed a Western Diet for 10 months started at 2 months of age, and subject to aortic‐banding for 6 months beginning at 6 months of age. Terminal studies were conducted at 12 months of age. Echocardiography was used to examine left ventricular (LV) mechanics (2‐dimensional speckle tracking) the week of terminal studies. RNA‐seq was performed on LV samples and Module Enrichment Analysis was performed on all expressed and varying genes, with networks generated using Ingenuity Pathway Analysis (IPA). qRT‐PCR was used to confirm RNA‐seq data, and group comparisons were made using a student's t‐test with significance reported at the P &lt; 0.10 and P &lt; 0.05 levels. IPA found enrichment of inflammatory and immune gene networks with significance to heart failure in WD‐AB animals. Gene interactions within these lists indicated activation of Pentraxin‐3 (PTX3) and interleukin 1 receptor‐like 1 (IL1RL1), which were chosen for validation given their potential relevance to HFpEF as inflammatory biomarkers. The approximate 5‐fold increase in PTX3 reported by RNA‐seq in WD‐AB compared to CON animals was confirmed separately using qRT‐PCR, as was an increase in IL1RL1 mRNA level. Both PTX3 and IL1RL1 mRNA levels (X‐axis) showed a significant negative correlation with LV apical early diastolic rotation rate (i.e. LV untwisting; Y‐axis), a 2D speckle tracking measure of diastolic function. Group means reflected a right and downward shift along the regression line for both PTX3 and IL1RL1 versus LV untwisting in the WD‐AB group compared to CON, indicating an increase in LV levels of these biomarkers is associated with a decline in LV diastolic mechanical function. In conclusion, WD‐AB animals express increased LV mRNA levels of the inflammatory biomarkers PTX3 and IL1RL1 that are significantly correlated with diastolic function. These data suggest studies in this Ossabaw pre‐clinical model may be useful for elucidating and testing biomarkers with diagnostic value potentially relevant to HFpEF.Support or Funding InformationHL112998 (CAE); VA‐Merit I01BX003271 (RSR); HL125503 (JP); HL136292 (TLD); HL122737, HL123295, &amp; HL129639 (YW).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Genetic regulation of IL1RL1 methylation and IL1RL1-a protein levels in asthma.

Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101).IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10-16) and serum IL1RL1-a levels (p=2.8×10-56). IL1RL1 methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.

Suppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction.

HomeJournal of the American Heart AssociationVol. 6, No. 9Suppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction Open AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessCorrectionPDF/EPUBSuppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction Originally published20 Sep 2017https://doi.org/10.1161/JAHA.117.002231Journal of the American Heart Association. 2017;6:e002231This article corrects the followingSoluble ST2 in Heart Failure With Preserved Ejection FractionCorrectionIn the article by AbouEzzeddine et al “Suppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction,” which published on February 18, 2017, and appeared in the February 2017 issue of the journal (J Am Heart Assoc. 2017;6:e004382. DOI: 10.1161/JAHA.116.004382.), the authors mistakenly referred to the ST2 as Suppression of Tumorigenicity 2, an entirely unrelated gene. The gene that is commonly reported as being a biomarker that is upregulated in heart failure and other systemic inflammatory diseases (and that the authors intended to refer to in this manuscript) is the gene IL1RL1 (interleukin 1 receptor like 1). Ambiguously, this was originally also termed ST2; hence the error that has been commonly made in the literature. The article has been corrected and all reference to Suppression of Tumorigenicity 2 has been corrected to Soluble ST2.The authors regret the error.The online version of the article has been updated and is available at http://jaha.ahajournals.org/content/6/2/e004382 Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zhang Q, Kang Y, Tang S and Yu C (2021) Intersection Between Diabetes and Heart Failure: Is SGLT2i the “One Stone for Two Birds” Approach?, Current Cardiology Reports, 10.1007/s11886-021-01591-3, 23:11, Online publication date: 1-Nov-2021. Nadar S and Shaikh M (2019) Biomarkers in Routine Heart Failure Clinical Care, Cardiac Failure Review, 10.15420/cfr.2018.27.2, 5:1, (50-56), Online publication date: 11-Feb-2019. Bayes-Genis A, Cediel G, Domingo M, Codina P, Santiago E and Lupón J (2022) Biomarkers in Heart Failure with Preserved Ejection Fraction, Cardiac Failure Review, 10.15420/cfr.2021.37, 8 Related articlesSoluble ST2 in Heart Failure With Preserved Ejection FractionMargaret M. Redfield, et al. Journal of the American Heart Association. 2017;6 September 22, 2017Vol 6, Issue 9Article InformationMetrics © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.https://doi.org/10.1161/JAHA.117.002231PMID: 28931528 Originally publishedSeptember 20, 2017 PDF download

Strand-specific RNA-sequencing analysis of multiple system atrophy brain transcriptome

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease. The major pathological hallmark of MSA is the accumulation of α-synuclein in oligodendrocytes. In contrast to Parkinson’s disease no definitive familial etiology for MSA has been determined. Yet, there is a growing body of evidence that perturbation of transcriptional processes leads to MSA pathology. Here we present the results of the first ribosomal-depleted strand-specific RNA-sequencing profile of the MSA brain frontal cortex tissue. Among the 123 differentially expressed genes over 50% were categorized as putative long intervening non-coding RNAs (lincRNAs). Along with the dysregulation of the non-coding portion of the transcriptome, the expression of protein coding genes was also affected, including serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 (SERPINA3), interleukin 1 receptor-like 1 (IL1RL1) and hemoglobin, beta (HBB). Also of interest was the alternative splicing of SNCA, along with the presence of an antisense transcript overlapping the 3′ exon of SNCA. Moreover, we demonstrate widespread antisense transcription throughout the frontal cortex that is largely not affected by MSA-specific neurodegenerative process. MSA causes a large disruption of lincRNAs in the human brain along with protein coding genes related to iron metabolism and immune response regulation. Most of the lincRNAs specific for MSA were novel. Hence our study uncovers another level of complexity in transcriptional pathology of MSA.

Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Subclinical Atherosclerosis in Rheumatoid Arthritis Patients.

ObjectivesTo determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA).MethodsA total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US).ResultsRA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed.ConclusionsIn conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA.

SST2 levels are associated with all‐cause mortality in anticoagulated patients with atrial fibrillation

Atrial fibrillation (AF) is associated with high morbidity and mortality, even despite the use of oral anticoagulation (OAC). Soluble suppression of tumorigenicity-2 (sST2) is a member of the interleukin-1 receptor family [interleukin-1 receptor-like 1 (IL1RL1)], which has been associated with an increased risk of mortality and morbidity in heart failure or acute coronary syndrome. We assessed the predictive value of sST2 levels in an unselected 'real-world' cohort of anticoagulated AF patients. We included 562 patients (49% male; median age 77 [IQR: 71-82]) with permanent AF who were stable (for at least 6 months) on OAC (INRs 2.0-3.0). sST2 levels were quantified by ELISA. Patients were followed-up for up to 4 years, and cardiovascular events and all-cause mortality were recorded. Median (IQR) of sST2 levels was 51.23 (39.09-67.40) μg/L. Median follow-up was 1587 days [IQR 1482-1617], and during this period, 91 patients died (16.2%, 3.72%/year). The c-statistic for predicting mortality with sST2 was 0.58 + 0.03; P = 0.017). On multivariate analysis, age [hazard ratio (HR) 1.09 (1.05-1.13); P < 0.001], diabetes mellitus [1.76 (1.08-2.88); P = 0.023], previous stroke [2.16 (1.29-3.60); P = 0.003] and sST2 levels [1.008 (1.002-1.14); P = 0.008] were independently associated with mortality. Concentrations of sST2 were also significantly associated with the risk of mortality, even after adjusting for the CHA2 DS2 -VASc score [HR: 1.007 (1.001-1.013); P = 0.014]. In an anticoagulated AF patient's cohort, sST2 levels are an independent predictive factor of all-cause mortality. sST2 levels could be a biomarker used to improve clinical risk assessment in anticoagulated AF patients.

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells.

Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33(95-270), IL-33(107-270), and IL-33(109-270), were 30-fold more potent than full-length human IL-33(1-270) for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33-dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66-111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33-mediated responses in allergic asthma and other inflammatory diseases.