Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung.

Allergic disease originates in early life and polymorphisms in interleukin-33 gene (IL33) and IL1RL1, coding for IL-33R and decoy receptor sST2, confer allergy risk. Early life T helper 2 (Th2) cell skewing and allergy susceptibility are often seen as remnants of feto-maternal symbiosis. Here we report that shortly after birth, innate lymphoid type 2 cells (ILC2s), eosinophils, basophils, and mast cells spontaneously accumulated in developing lungs in an IL-33-dependent manner. During the phase of postnatal lung alveolarization, house dust mite exposure further increased IL-33, which boosted cytokine production in ILC2s and activated CD11b+ dendritic cells (DCs). IL-33 suppressed IL-12p35 and induced OX40L in neonatal DCs, thus promoting Th2 cell skewing. Decoy sST2 had a strong preventive effect on asthma in the neonatal period, less so in adulthood. Thus, enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a period of maximal lung remodeling.

Multiomics analysis identified IL-4-induced IL1RL1high eosinophils characterized by prominent cysteinyl leukotriene metabolism.

BACKGROUND: Clinical studies have demonstrated that IL-4, a type 2 cytokine, plays an important role in the pathogenesis of chronic rhinosinusitis and eosinophilic asthma. However, the direct effect of IL-4 on eosinophils remains unclear. OBJECTIVE: We aimed to elucidate the inflammatory effects of IL-4 on the functions of human eosinophils. METHODS: A multiomics analysis comprising transcriptomics, proteomics, lipidomics, quantitative RT-PCR, and flow cytometry was performed by using blood eosinophils from healthy subjects stimulated with IL-4, IL-5, or a combination thereof. RESULTS: Transcriptomic and proteomic analyses revealed that both IL-4 and IL-5 upregulate the expression of γ-gultamyl transferase 5, a fatty acid-metabolizing enzyme that converts leukotriene C4 into leukotriene D4. In addition, IL-4 specifically upregulates the expression of IL-1 receptor-like 1 (IL1RL1), a receptor for IL-33 and transglutaminase-2. Additional transcriptomic analysis of cells stimulated with IL-13 revealed altered gene expression profiles, characterized by the upregulation of γ-gultamyl transferase 5, transglutaminase-2, and IL1RL1. The IL-13-induced changes were not totally different from the IL-4-induced changes. Lipidomic analysis revealed that IL-5 and IL-4 additively increased the extracellular release of leukotriene D4. In vitro experiments revealed that STAT6 and IL-4 receptor-α control the expression of these molecules in the presence of IL-4 and IL-13. Analysis of eosinophils derived from patients with allergic disorders indicated the involvement of IL-4 and IL-13 at the inflamed sites. CONCLUSIONS: IL-4 induces the proallergic phenotype of IL1RL1high eosinophils, with prominent cysteinyl leukotriene metabolism via STAT6. These cellular changes represent potential therapeutic targets for chronic rhinosinusitis and eosinophilic asthma.

Increased expression of IL1-RL1 is associated with type 2 and type 1 immune pathways in asthma.

BACKGROUND: Asthma is a common chronic airway disease in the world. The purpose of this study was to explore the expression of IL1-RL1 in sputum and its correlation with Th1 and Th2 cytokines in asthma. METHODS: We recruited 132 subjects, detected IL1-RL1 protein level in sputum supernatant by ELISA, and analyzed the correlation between the expression level of IL1-RL1 and fraction of exhaled nitric oxide (FeNO), IgE, peripheral blood eosinophil count (EOS#), and Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-33 and TSLP) and Th1 cytokines (IFN-γ, IL-2, IL-8). The diagnostic value of IL1-RL1 was evaluated by ROC curve. The expression of IL1-RL1 was further confirmed by BEAS-2B cell in vitro. RESULTS: Compared with the healthy control group, the expression of IL1-RL1 in sputum supernatant, sputum cells and serum of patients with asthma increased. The AUC of ROC curve of IL1-RL1 in sputum supernatant and serum were 0.6840 (p = 0.0034), and 0.7009 (p = 0.0233), respectively. IL1-RL1 was positively correlated with FeNO, IgE, EOS#, Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-33 and TSLP) and Th1 cytokines (IFN-γ, IL-2, IL-8) in induced sputum supernatant. Four weeks after inhaled glucocorticoids (ICS) treatment, the expression of IL1-RL1 in sputum supernatant and serum was increased. In vitro, the expression of IL1-RL1 in BEAS-2B was increased after stimulated by IL-4 or IL-13 for 24 h. CONCLUSION: The expression of IL1-RL1 in sputum supernatant, sputum cells and serum of patients with asthma was increased, and was positively correlated with some inflammatory markers in patients with asthma. IL1-RL1 may be used as a potential biomarker for the diagnosis and treatment of asthma.

Association between IL1RL1 gene polymorphisms and allergic rhinitis risk in the Chinese Han population.

BACKGROUND: Although it has been confirmed that IL1RL1 is involved in the occurrence of allergic rhinitis (AR), the role of IL1RL1 gene single nucleotide polymorphisms (SNPs) in AR is still unclear. METHODS: We performed a case-control study including 1000 AR patients and 1000 healthy controls. The four SNPs rs72823628 G > A, rs950881 G > T, rs72823641 T > A and rs3771175 T > A in IL1RL1 were chosen and genotyped using Agena MassARRAY platform. The relationship between IL1RL1 SNPs and AR risk was analyzed by logistic regression and assessed with odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). RESULTS: Overall analysis revealed that IL1RL1 gene rs72823628, rs950881 and rs3771175 were associated with a reduced AR risk. Stratified analysis showed that the three SNPs (rs72823628, rs950881 and rs3771175) were obviously linked to a reduced risk of AR in males. Moreover, no correlation was observed between haplotypes and reduced AR risk after the false discovery rate (FDR) correction. The false positive report probability (FPRP) analysis was used to further validate significant findings. CONCLUSION: Our study is the first to indicate that IL1RL1 gene polymorphisms (rs72823628, rs950881 and rs3771175) may be correlated with decreased risk of AR in the Chinese Han population.

Interleukin 1 receptor-like 1 rs13408661/13431828 polymorphism is associated with persistent post-bronchiolitis asthma at school age.

AIM: Interleukin (IL) 1 receptor-like 1, encoded by the IL1RL1 gene, is a receptor for IL-33. In European birth cohorts, IL1RL1 rs102082293, rs10204137 (rs4988955), rs13424006 and rs13431828 (rs13048661) variations were associated with asthma at school age. In a Dutch multi-centre study, IL1RL1 rs1921622 variation was associated with severe bronchiolitis. We evaluated the associations of these five IL1RL1 variations with asthma and lung function at school age after hospitalisation for bronchiolitis in infancy. METHODS: Follow-up data, including impulse oscillometry at age 5-7 and flow-volume spirometry at age 11-13 years, and the IL1RL1 genotype data were available for 141 children followed until 5-7 and for 125 children followed until 11-13 age years after bronchiolitis in infancy. The IL1RL1 rs10204137 and rs4988955, and the IL1RL1 rs13048661 and rs13431828, are 100% co-segregating in the Finnish population. RESULTS: The variant IL1RL1 rs13048661/13431828 genotype was constantly associated with increased asthma risk by various definitions at 5-7 and 11-13 years of ages. The result was confirmed with analyses adjusted for current confounders and early-life environment-related factors. Statistical significances were lost, when maternal asthma and atopic dermatitis in infancy were included in the model. CONCLUSION: IL1RL1 rs13048661/13431828 variation was associated with post-bronchiolitis asthma outcomes at school age.

The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma.

Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V-) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V- MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients.

Genome sequencing unveils mutational landscape of the familial Mediterranean fever: Potential implications of IL33/ST2 signalling.

Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease. It is transmitted as autosomal recessive trait with mutations in MEditerranean FeVer (MEFV) gene. Despite a typical clinical expression, many patients have either a single or no mutation in MEFV. The current work is aimed to revisit the genetic landscape of FMF disease using high-coverage whole genome sequencing. In atypical patients (carrying a single or no mutation in MEFV), we revealed many rare variants in genes associated with auto-inflammatory disorders, and more interestingly, we discovered a novel variant ( a 2.1-Kb deletion) in exon 11 of IL1RL1 gene, present only in patients. To validate and screen this patient-specific variant, a tandem of allele-specific PCR and quantitative real-time PCR was performed in 184 FMF patients and 218 healthy controls and we demonstrated that the novel deletion was absent in controls and was present in more than 19% of patients. This study sheds more light on the mutational landscape of FMF. Our discovery of a disease-specific variant in IL1RL1 gene may constitute a novel genetic marker for FMF. This finding suggesting a potential role of the IL33/ST2 signalling in the disease pathogenicity highlights a new paradigm in FMF pathophysiology.

Associations of IL1RAP and IL1RL1 gene polymorphisms with obesity and inflammation mediators.

OBJECTIVES: Obesity is attributable to high free fatty acids, ER stress, oxidative stress and inflammation. The expression of IL-33, IL-1RL1 and IL-1RAP gene was observed in human visceral white fats, pre-adipocytes and adipocytes. The aim of this study was to determine whether IL1RAP and IL1RL1 gene variants were associated with obesity and inflammation mediators. METHODS: 3 SNPs of IL1RAP (rs9990107, rs3836449 and rs9290936) and 11 SNPs of IL1RL1 (rs3771180, rs13431828, rs3214363, rs1420101, rs12905, rs3771175, rs3821204, rs12712142, rs10204137, rs4988958, and rs10206753) were genotyped for 175 obesity (BMI ≥ 25) and 358 non-obesity (BMI < 25.0) subjects. The genotype of SNPs was determined by the Axiom Genome-Wide Human Assay. RESULTS: The allele and genotype frequencies of 2 SNPs in the IL1RAP gene (rs9990107 and rs3836449) and 11 SNPs in the IL1RL1 gene (rs3771180, rs13431828, rs3214363, rs1420101, rs12905, rs3771175, rs3821204, rs12712142, rs10204137, rs4988958 and rs10206753) were significantly associated between the obesity and non-obesity groups. The two haplotypes (GCTTATGAATT and TT-CGACCGCC) in block1 were associated with obesity. In the non-obesity group, genotype frequencies of rs3771180, rs13431828, rs3214363, rs10204137, rs4988958 and rs10206753 SNPs of IL1RL1 showed significant differences in the dominant models in lymphatic cell percentage. The genotype frequencies of rs1420101, rs21905, rs3821024 and rs12712142 SNPs of IL1RL1 showed significant differences in the dominant models in eosinophil percentage. CONCLUSIONS: Our results suggest that IL1RAP and IL1RL1 gene polymorphisms may be associated with obesity and inflammation mediators.

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.

IL-33 in T Cell Differentiation, Function, and Immune Homeostasis.

Recent studies have highlighted a role for the alarmin interleukin (IL)-33 in CD4(+) and CD8(+) T cell activation and function, and have also revealed important distinctions. The IL-33 receptor ST2 is constitutively and abundantly expressed on T-helper-2 (Th2) and GATA-3(+) regulatory T cells in a GATA-3- and STAT5-dependent manner. Upon activation, Th1 and cytotoxic T cells express ST2 transiently, driven by T-bet and/or STAT4. We review these findings here, and critically examine evidence indicating that IL-33 enhances the differentiation and functionality of various T cell subsets through positive feedback loops involving lineage-specifying transcription factors. In this context, we discuss how quantitative and qualitative differences in ST2 expression between effector and GATA-3(+) regulatory T cells may contribute to immune homeostasis, and outline important areas of future inquiry.

Association of IL1RL1 rs3771180 and TSLP rs1837253 variants with asthma in the Guangxi Zhuang population in China.

OBJECTIVE: IL-1 receptor-like 1 (IL1RL1) and thymic stromal lymphopoietin (TSLP) play important roles in asthma in various ways. IL1RL1 rs3771180 and TSLP rs1837253 single nucleotide polymorphisms (SNPs) are associated with asthma in some European nationals but not in Zhuang people. Accordingly, this study aimed to determine the associations of IL1RL1 rs3771180 and TSLP rs1837253 with asthma in Zhuang people. METHODS: We performed a case-control study to observe the association between the two polymorphisms and asthma in a Guangxi Zhuang cohort consisting of 123 asthmatic patients and 100 healthy controls. These individuals were recruited from the Department of Respiration of the First Affiliated Hospital of Guangxi Medical University. Multiplex PCR assay was used to identify the genotype of rs3771180 and rs1837253. Data were analyzed with SPSS 22.0 and SHEsis. RESULTS: rs1837253 showed significant differences between asthmatic and control groups in allele comparison (OR = 2.15; 95% CI = 1.27-3.63; P = 0.004), as well as in the homozygote (OR = 4.83; 95% CI = 1.47-16.47; P = 0.012), heterozygote (OR = 2.69; 95% CI = 1.20-6.00; P = 0.016), and dominant (OR = 3.01; 95% CI = 1.39-6.52; P = 0.005) genetic models. However, the genotype frequencies of rs3771180 did not obviously differ. CONCLUSION: rs1837253 is associated with asthma susceptibility and may increase the risk of asthma in Zhuang people in Guangxi.

Proteomic analysis of serum proteins from HIV/AIDS patients with Talaromyces marneffei infection by TMT labeling-based quantitative proteomics.

BACKGROUND: Talaromyces marneffei (TM) is an emerging pathogenic fungus that can cause a fatal systemic mycosis in patients infected with human immunodeficiency virus (HIV). Although global awareness regarding HIV/TM coinfection is increasing little is known about the mechanism that mediates the rapid progression to HIV/AIDS disease in coinfected individuals. The aim of this study was to analyze the serum proteome of HIV/TM coinfected patients and to identify the associated protein biomarkers for TM in patients with HIV/AIDS. METHODS: We systematically used multiplexed isobaric tandem mass tag labeling combined with liquid chromatography mass spectrometry (LC-MS/MS) to screen for differentially expressed proteins in the serum samples from HIV/TM-coinfected patients. RESULTS: Of a total data set that included 1099 identified proteins, approximately 86% of the identified proteins were quantified. Among them, 123 proteins were at least 1.5-fold up-or downregulated in the serum between HIV/TM-coinfected and HIV-mono-infected patients. Furthermore, our results indicate that two selected proteins (IL1RL1 and THBS1) are potential biomarkers for distinguishing HIV/TM-coinfected patients. CONCLUSIONS: This is the first report to provide a global proteomic profile of serum samples from HIV/TM-coinfected patients. Our data provide insights into the proteins that are involved as host response factors during infection. These data shed new light on the molecular mechanisms that are dysregulated and contribute to the pathogenesis of HIV/TM coinfection. IL1RL1 and THBS1 are promising diagnostic markers for HIV/TM-coinfected patients although further large-scale studies are needed. Thus, quantitative proteomic analysis revealed molecular differences between the HIV/TM-coinfected and HIV-mono-infected individuals, and might provide fundamental information for further detailed investigations.

MYB-GATA1 fusion promotes basophilic leukaemia: involvement of interleukin-33 and nerve growth factor receptors.

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloblastic leukaemia. We previously described a recurrent t(X;6)(p11;q23) translocation generating an MYB-GATA1 fusion gene in male infants with ABL. To better understand its role, the chimeric MYB-GATA1 transcription factor was expressed in CD34-positive haematopoietic progenitors, which were transplanted into immunodeficient mice. Cells expressing MYB-GATA1 showed increased expression of markers of immaturity (CD34), of granulocytic lineage (CD33 and CD117), and of basophilic differentiation (CD203c and FcϵRI). UT-7 cells also showed basophilic differentiation after MYB-GATA1 transfection. A transcriptomic study identified nine genes deregulated by both MYB-GATA1 and basophilic differentiation. Induction of three of these genes (CCL23, IL1RL1, and NTRK1) was confirmed in MYB-GATA1-expressing CD34-positive cells by reverse transcription quantitative polymerase chain reaction. Interleukin (IL)-33 and nerve growth factor (NGF), the ligands of IL-1 receptor-like 1 (IL1RL1) and neurotrophic receptor tyrosine kinase 1 (NTRK1), respectively, enhanced the basophilic differentiation of MYB-GATA1-expressing UT-7 cells, thus demonstrating the importance of this pathway in the basophilic differentiation of leukaemic cells and CD34-positive primary cells. Finally, gene reporter assays confirmed that MYB and MYB-GATA1 directly activated NTRK1 and IL1RL1 transcription, leading to basophilic skewing of the blasts. MYB-GATA1 is more efficient than MYB, because of better stability. Our results highlight the role of IL-33 and NGF receptors in the basophilic differentiation of normal and leukaemic cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Proteogenomic analysis of NCC-S1M, a gastric cancer stem cell-like cell line that responds to anti-PD-1.

To elucidate signaling pathways that regulate gastric cancer stem cell (CSC) phenotypes and immune checkpoint, we performed a proteogenomic analysis of NCC-S1M, which is a gastric cancer cell line with CSC-like characteristics and is the only syngeneic gastric tumor cell line transplant model created in the scientific community. We found that the NCC-S1M allograft was responsive to anti-PD-1 treatment, and overexpressed Cd274 encoding PD-L1. PD-L1 was transcriptionally activated by loss of the TGF-ß signaling. Il1rl1 protein was overexpressed in NCC-S1M cells compared with NCC-S1 cells that are less tumorigenic and less chemoresistant. Il1rl1 knockdown in NCC-S1M cells reduced tumorigenic potential and in vivo chemoresistance. Our proteogenomic analysis demonstrates a role of Smad4 loss in the PD-L1 immune evasion, as well as Il1rl1's role in CSC-like properties of NCC-S1M.

The challenge of measuring IL-33 in serum using commercial ELISA: lessons from asthma.

BACKGROUND: Interleukin-33 (IL-33) has been subject of extensive study in the context of inflammatory disorders, particularly in asthma. Many human biological samples, including serum, have been used to determine the protein levels of IL-33, aiming to investigate its involvement in asthma. Reliable methods are required to study the association of IL-33 with disease, especially considering the complex nature of serum samples. OBJECTIVE: We evaluated four IL-33 ELISA kits, aiming to determine a robust and reproducible approach to quantifying IL-33 in human serum from asthma patients. METHODS: IL-33 levels were investigated in serum of well-defined asthma patients by the Quantikine, DuoSet (both R&D systems), ADI-900-201 (Enzo Life Sciences), and SKR038 (GenWay Biotech Inc San Diego USA) immunoassays, as well as spiking experiments were performed using recombinant IL-33 and its soluble receptor IL-1RL1-a. RESULTS: We show that 1) IL-33 is difficult to detect by ELISA in human serum, due to lack of sensitivity and specificity of currently available assays; 2) human serum interferes with IL-33 quantification, in part through IL-1RL1-a; and 3) using non-serum certified kits may lead to spurious findings. CONCLUSION AND CLINICAL RELEVANCE: If IL-33 is to be studied in the serum of asthma patients and other diseases, a more sensitive and specific assay method is required, which will be vital for further understanding and targeting of the IL-33/IL-1RL1 axis in human disease.

Phenotypic and genotypic association of epithelial IL1RL1 to human TH2-like asthma.

BACKGROUND: Severe asthma remains poorly characterized, although it likely consists of at least 1 phenotype with features of TH2-like inflammation. IL1RL1, encoding both the IL-33 receptor, ST2L, and decoy receptor, sST2, has been genetically associated with asthma, though the mechanism for susceptibility remains unknown. OBJECTIVE: Given previous data supporting a role for IL1RL1 in TH2 inflammation, we hypothesized that ST2L expression might be increased in TH2-like asthma and that expression levels would be associated with single nucleotide polymorphisms in IL1RL1, possibly explaining its genetic relationship with asthma. We also sought to evaluate the regulation of ST2L and sST2 in vitro. METHODS: Endobronchial brushings and biopsies were obtained and expression of ST2L compared by severity levels, as well as by TH2-like biomarkers. Subjects were genotyped and the relationship of dichotomous expression of ST2L and sST2 to single nucleotide polymorphisms in IL1RL1 were determined. Epithelial cells were grown in air-liquid interface culture, and ST2L and sST2 responses to IFN-γ and IL-13 were evaluated. RESULTS: ST2L expression was increased in severe asthma (P = .02) and associated with multiple indicators of TH2-like inflammation, including blood eosinophils (P = .001), exhaled nitric oxide (P = .003), and epithelial CLCA1 (P < .0001) and eotaxin-3 (P = .001) mRNA expression. Multiple single nucleotide polymorphisms in IL1RL1 were found in relation to dichotomous expression of both ST2L and sST2. sST2 expression was associated with IFN-γ expression in bronchoalveolar lavage, while inducing its expression in vitro in primary human epithelial cells. CONCLUSION: Both pathologic and genetic approaches support a role for IL1RL1 in severe asthma, as well as TH2-lke asthma, suggesting that targeting this pathway may have therapeutic benefits.

Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.

BACKGROUND: Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. OBJECTIVE: In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. METHODS: Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. RESULTS: Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. CONCLUSIONS: IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.

The variations in the IL1RL1 gene and susceptibility to preeclampsia.

The IL1RL1, which encodes at least three isoforms by alternative splicing, has been identified to be involved in the initiation and perpetuation of inflammation. In spite of being a main contributor of maternal and perinatal mortality, the mechanism responsible for the pathophysiology of preeclampsia has not yet been well addressed. To investigate the relationship between IL1RL1 polymorphisms and preeclampsia risk, we identified the correlation between three tag SNPs (rs13017455, rs1420103 and rs17027006) in IL1RL1 with preeclampsia risk in a case-control study. A total of 214 cases and 208 controls were recruited to participate in this study. Genotypes of the three SNPs were determined with the use of polymerase chain reaction-restriction fragment length polymorphism assay. Significantly reduced preeclampsia risk was found to be associated with the CT genotype of rs13017455 (p = 0. 032, OR = 0. 66, 95% CI = 0.45-0.97) in overdominant model. Differences were particularly significant in the severe preeclampsia subgroup (p = 0.045, OR = 0.66, 95% CI = 0.44-0.99) and the early-onset severe preeclampsia subgroup (p = 0.0097, OR = 0.47, 95% CI = 0.26-0.84). Significantly increased mild preeclampsia risk was observed associated with GG genotype of rs1420103 polymorphisms (p = 0.029, OR = 2.18, 95% CI = 1.09-4.34), while reducing late-onset severe preeclampsia susceptibility was associated with TT genotype of rs1420103 (p = 0.02, OR = 0.49, 95% CI = 0.26-0.92).

ST2-Mediated Neutrophilic Airway Inflammation: A Therapeutic Target for Patients With Uncontrolled Asthma.

PURPOSE: Suppression of tumorigenicity 2 (ST2) has been proposed as the receptor contributing to neutrophilic inflammation in patients with type 2-low asthma. However, the exact role of ST2 in neutrophil activation remains poorly understood. METHODS: A total of 105 asthmatic patients (classified into 3 groups according to control status: the controlled asthma [CA], partly-controlled asthma [PA], and uncontrolled asthma [UA] groups), and 104 healthy controls were enrolled to compare serum levels of soluble ST2 (sST2) and interleukin (IL)-33. Moreover, the functions of ST2 in neutrophils and macrophages (Mϕ) were evaluated ex vivo and in vivo. RESULTS: Serum sST2 levels were significantly higher in the UA group than in the CA or PA groups (P < 0.05 for all) with a negative correlation between serum sST2 and forced expiratory volume in 1 second % (r = -0.203, P = 0.038). Significantly higher expression of ST2 receptors on peripheral neutrophils was noted in the UA group than in the PA or CA groups. IL-33 exerted its effects on the production of reactive oxygen species, the formation of extracellular traps from neutrophils, and Mϕ polarization/activation. In neutrophilic asthmatic mice, treatment with anti-ST2 antibody significantly suppressed proinflammatory cytokines (tumor necrosis factor-alpha and IL-17A) as well as the numbers of immune cells (neutrophils, Mϕ, and group 3 innate lymphoid cells) in the lungs. CONCLUSIONS: These results suggest that IL-33 induces the activation of neutrophils and Mϕ via ST2 receptors, leading to neutrophilic airway inflammation and poor control status of asthma. ST2 could be a therapeutic target for neutrophilic airway inflammation in patients with UA.

IL1RL1 polymorphisms rs12479210 and rs1420101 are associated with increased lung cancer risk in the Chinese Han population.

Background: Lung cancer is one of the most common human malignant diseases. In this study, we aimed to explore the association between IL1RL1 genetic polymorphisms and lung cancer risk in the Chinese Han population. Methods: We selected and genotyped six SNPs in the IL1RL1 gene using the Agena MassARRAY system in 507 lung cancer patients and 507 healthy controls. The association between IL1RL1 variants and lung cancer risk was assessed using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Multi-factor dimensionality reduction (MDR) was used to analyze the impact of SNP-SNP interactions on the risk of lung cancer. Results: The results of overall analysis indicated that rs12479210 (T vs. C: OR = 1.42, FDR-p = 0.002; TC vs. CC: OR = 1.70, FDR-p < 0.0001; TT vs. CC: OR = 1.77, FDR-p = 0.032; TT-TC vs. CC: OR = 1.71, FDR-p = 0.001; additive: OR = 1.44, FDR-p = 0.001) and rs1420101 (T vs. C: OR = 1.31, FDR-p = 0.036; TT-TC vs. CC: OR = 1.42, FDR-p = 0.031; additive: OR = 1.30, FDR-p = 0.030) were associated with an increased the risk of lung cancer among the Chinese Han population. Stratified analysis also found the association between these two SNPs and lung cancer risk. However, there were no significant association observed between the other four SNPs (rs3771180, rs3771175, rs10208293, and rs10197862) in IL1RL1 and lung cancer risk. Furthermore, MDR analysis showed that rs12479210 was the best single model with the highest testing accuracy (0.566) and perfect CVC (10/10) for predicting lung cancer risk. The expression level of the IL1RL1 gene is lower in lung cancer tissue than normal tissue, and there are significant differences in the expression levels of IL1RL1 between rs12479210 and rs1420101 genetypes in lung cancer tissue (p < 0.05). Conclusion: Our findings suggest that IL1RL1 genetic variants (rs12479210 and rs1420101) are associated with an increased lung cancer risk in the Chinese Han population. These risk variants may serve as biomarkers for the prevention and treatment of lung cancer.