Interleukin-1 Receptor Type 2 Research Articles

Identification of candidate hub genes for COVID-19-induced idiopathic pulmonary fibrosis by bioinformatic analysis

Background: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterized by progressive scarring leading to alveolar stiffness, and reduced lung capacity, which might be induced by Coronavirus Disease 2019 (COVID-19). This study aims to explore the molecular mechanism of COVID-19-induced IPF and find the immune changes in the process of IPF. Methods: The data from the GEO database were processed by using the R algorithm package to explore the correlation between COVID-19 and IPF. Differential analysis, Venn analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, immune infiltration analysis, transcriptional analysis, and protein-protein analysis were performed to find the candidate hub genes, related pathways, and immune cell changes in IPF. Results: 69 differentially expressed genes (DGEs) were identified by differential analysis, including 27 up-regulated genes and 42 down-regulated genes. 15 hub genes were identified, which are CEA Cell Adhesion Molecule 8 (CEACAM8), Cathelicidin Antimicrobial Peptide (CAMP), Ribosomal Protein L9 (RPL9), Lactotransferrin (LTF), CD177 Molecule (CD177), Annexin A3 (ANXA3), CD3 Delta Subunit Of T-Cell Receptor Complex (CD3D), Granulin Precursor (GRN), Granzyme A (GZMA), Granzyme K (GZMK), Interleukin 1 Receptor Type 2 (IL1R2), Lipocalin 2 (LCN2), Matrix Metallopeptidase 9 (MMP9), Neural EGFL Like 2 (NELL2) and Ribosomal Protein L4 (RPL4), among which ANXA3, IL1R2, MMP9, LCN2, NELL2 might be the most significant candidate genes for COVID-19-induced IPF. The transcriptional factors of hub genes were found to be related to Sp1 Transcription Factor (SP1), Signal Transducer And Activator Of Transcription 1 (STAT1), RELA Proto-Oncogene, NF-KB Subunit (RELA), and Nuclear Factor Kappa B Subunit 1 (NFKB1). Immune cell analysis revealed that Plasma cells, Macrophages MO, Dendritic cells activated, Mast cells resting, and Eosinophils were significantly elevated in the IPF compared with healthy subjects. Conclusions: The findings shed light on the risk factors of COVID-19 in the development of IPF, and immune changes in COVID-19 and IPF. The shared DEGs might be prognostic in the treatment of IPF.

IL1R2 promotes retinal angiogenesis to participate in retinopathy of prematurity by activating the HIF1α/PFKFB3 pathway

Retinopathy of prematurity (ROP) is the leading cause of blindness in children, but there is no safe and effective treatment available. Interleukin-1 receptor type 2 (IL1R2) acts as a decoy receptor for IL-1 may affect ROP progression. This study aimed to investigate the role of IL1R2 in ROP. A microglial cell model was established under hypoxia conditions and co-cultured with choroidal endothelial cells, while an oxygen-induced retinopathy (OIR) model was also established. Microglial activation and IL1R2 levels in retinal tissues were analyzed using immunofluorescence assay. Endothelial cell migration was evaluated by Transwell assay and scratch test, angiogenesis was assessed using ELISA and tube formation assay, and proliferation was evaluated by EdU assay. The HIF1α/PFKFB3 pathway was analyzed by western blot. We observed that IL1R2 expression was predicted to be upregulated in ROP and was increased in hypoxia-treated BV2 cells. Additionally, IL1R2 levels were upregulated in the retinal tissues of OIR mice and correlated with microglial activation. In vitro experiments, we found that hypoxia promoted endothelial cell migration, angiogenesis, proliferation, and activated the HIF1α/PFKFB3 pathway, which were rescued by IL1R2 knockdown. Moreover, NHWD-870 (a HIF1α/PFKFB3 pathway inhibitor) suppressed endothelial cell migration, angiogenesis, and proliferation induced by IL1R2 overexpression. In conclusion, IL1R2 facilitates the migration, angiogenesis, and proliferation of choroidal endothelial cells by activating the HIF1α/PFKFB3 pathway to regulate ROP progression.

Relationships among gut microbes, the interleukin family, and hypertension: a mediation Mendelian randomization study

PurposeObservational studies have increasingly recognized the influence of gut microbes on blood pressure modulation. Despite these findings, a direct causal link between gut flora and hypertension remains unestablished due to inherent confounders and the challenges of reverse causality in observational research. In this study, we sought to elucidate the causal relationship between specific gut flora and hypertension and its intermediary mediators.MethodsWe employed a two-sample Mendelian randomization (MR) and mediation MR analysis, analyzing 211 species of gut bacteria, with a focus on the interleukin family as potential mediators and hypertension as the primary outcome. The central methodological technique was inverse variance-weighted estimation, supplemented by various other estimators.ResultsOur findings revealed that two bacterial species positively correlated with hypertension risk, while five exhibited a negative association. Further validation was conducted using sensitivity analyses. Notably, our mediation MR results suggest interleukin-1 receptor type 2 (IL-1R2) as a mediator for the effect of the genus Clostridium innocuum group on hypertension, accounting for a mediation proportion of 14.07% [mediation effect: (b = 0.0007, 95%CI: 0.0002–0.0011); proportion mediation = 14.07% (4.26–23.40%)].ConclusionOur research confirms a genetic causal relationship between specific gut microbes and hypertension, emphasizing the potential mediating role of interleukin-1 receptor type 2 (IL-1R2) and offering insights for clinical hypertension interventions.

Construction of lncRNA-miRNA-mRNA regulatory network in severe asthmatic bronchial epithelial cells: A bioinformatics study.

Asthma is a chronic respiratory disease caused by environment-host interactions. Bronchial epithelial cells (BECs) are the first line of defense against environmental toxins. However, the mechanisms underlying the role of BECs in severe asthma (SA) are not yet fully understood. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have been shown to play important roles in the regulation of gene expression in the pathogenesis of SA. In this study, bioinformatics was used for the first time to reveal the lncRNA-miRNA-mRNA regulatory network of BECs in SA. Five mRNA datasets of bronchial brushing samples from patients with SA and healthy controls (HC) were downloaded from the Gene Expression Omnibus (GEO) database. A combination of the Venn diagram and robust rank aggregation (RRA) method was used to identify core differentially expressed genes (DEGs). Protein-protein interaction (PPI) analysis of core DEGs was performed to screen hub genes. The miRDB, miRWalk, and ENCORI databases were used to predict the miRNA-mRNA relationships, and the ENCORI and starBase v2.0 databases were used to predict the upstream lncRNAs of the miRNA-mRNA relationships. Four core DEGs were identified: carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), interleukin-1 receptor type 2 (IL1R2), trefoil factor 3 (TFF3), and vascular endothelial growth factor A (VEGFA). These 4 core DEGs indicated that SA was not significantly associated with sex. Enrichment analysis showed that the MAPK, Rap1, Ras, PI3K-Akt and Calcium signaling pathways may serve as the principal pathways of BECs in SA. A lncRNA-miRNA-mRNA regulatory network of the severe asthmatic bronchial epithelium was constructed. The top 10 competing endogenous RNAs (ceRNAs) were FGD5 antisense RNA 1 (FGD5-AS1), metastasis associated lung adenocarcinoma transcript 1 (MALAT1), X inactive specific transcript (XIST), HLA complex group 18 (HCG18), small nucleolar RNA host gene 16 (SNHG16), has-miR-20b-5p, has-miR-106a-5p, hsa-miR-106b-5p, has-miR-519d-3p and Fms related receptor tyrosine kinase 1 (FLT1). Our study revealed a potential mechanism for the lncRNA-miRNA-mRNA regulatory network in BECs in SA.

Oridonin employs interleukin 1 receptor type 2 to treat noise-induced hearing loss by blocking inner ear inflammation

NOD-like receptor protein 3 (NLRP3) inflammasomes trigger the inflammatory cascades and participate in various inflammatory diseases, including noise-induced hearing loss (NIHL) caused by oxidative stress. Recently, the anti-inflammatory traditional medicine oridonin (Ori) has been reported to provide hearing protection in mice after noise exposure by blocking the NLRP3-never in mitosis gene A-related kinase 7 (NEK7)-inflammasome complex assembly. Using RNA sequencing analysis, we further elucidated that interleukin 1 receptor type 2 (IL1R2) may be another crucial factor regulated by Ori to protect NIHL. We observed that IL1R2 expression was localized in spiral ganglion neurons, inner and outer hair cells, in Ori-treated mouse cochleae. Additionally, we confirmed that ectopic overexpression of IL1R2 in the inner ears of healthy mice using an adeno-associated virus delivery system significantly reduced noise-induced ribbon synapse lesions and hearing loss by blocking the “cytokine storm” in the inner ear. This study provides a novel theoretical foundation for guiding the clinical treatment of NIHL.

Molecular and functional characterization of chicken interleukin 1 receptor 2 (chIL-1R2)

Interleukin-1 receptor type 2 (IL1R2) is a decoy receptor for exogenous IL-1. However, its functional role in chicken immunity is poorly understood. Herein, chicken IL-1R2 (chIL-1R2) was identified and functionally characterized in vivo and in vitro. The chIL-1R2 coding sequence includes 1,236 nucleotides encoding 412 amino acids, is highly conserved, and has a close relationship with its mammalian counterpart. Its extracellular region has three Ig-like domains but no TIR domain for intracellular signaling. Using ELISA, the recombinant chIL-1R2 protein was demonstrated to specifically bind to the chicken IL-1β. ChIL-1R2 mRNA expression was shown to be higher in the spleen, lung, kidney, small intestine, and liver. The expression of chIL-1R2 and chIL-1R1 was significantly upregulated in DF-1 cells treated with poly (I:C), but significantly downregulated in the presence of NF-κB, JNK, and MEK inhibitors, indicating that the NF-κB, JNK, and MEK signaling pathways are required for the transcriptional regulation of chIL-1R1 and chIL-1R2 expression. It is worth noting that while the p30 MAPK pathway was required for chIL-1R1 expression, it was not required for chIL-1R2 expression. Furthermore, chIL-1R2 expression increased as early as day 1, and then significantly decreased until day 3, while chIL-1R1 was dramatically upregulated in four organs of chickens infected with the highly pathogenic avian influenza virus (HPAIV). These findings indicate that chIL-1R1 and chIL-1R2 may play a crucial in innate and adaptive immune responses toward HPAIV infection. In summary the present study showed that chIL-1R2 binds to chIL-1β antibody. ChIL-1R2 expression can be induced by a viral infection, and may be regulated through NF-κB/JNK/MEK-mediated signaling pathways.

IL1R2 promotes tumor progression via JAK2/STAT3 pathway in human clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is known as the most aggressive subtype of genitourinary cancers. The lack of effective therapies has prompted us to further explore the complex network of genes involved in ccRCC tumor progression and metastasis and to seek new biomarkers and therapeutic strategies to improve clinical outcomes. Interleukin-1 receptor type 2 (IL1R2), a decoy receptor of IL-1, is found to be differentially expressed in various tumors types recently. However, the role of IL1R2 in ccRCC has not been documented. Herein, we found that the expression of IL1R2 in ccRCC tissues was significantly increased as the tumor’s Furman pathological grade was elevated. Compared to lower IL1R2 expression, ccRCC patients with high IL1R2 expression had a significantly worse OS rate. IL1R2 could serve as an independent prognostic predictor for ccRCC patients. Depletion of IL1R2 could inhibit cell proliferation, migration, invasion, and cell cycle arrest at the G1 phase, while overexpression of IL1R2 could reverse this effect. Moreover, depletion of IL1R2 led to changes and enrichment of several signaling pathways, as shown by RNA sequencing. We subsequently verified that Janus kinase 2 / signal transducer and activator of transcription 3 (JAK2/STAT3) pathway was involved in the IL1R2 mediated regulation of cellular functions of ccRCC cells and these functions were acted by the intracellular domain of IL1R2, not the extracellular domain. Our findings suggested that IL1R2 could serve as a potential therapeutic target for ccRCC progression and metastasis via its regulation of the JAK2/STAT3 signaling pathway.

Cardiomyocyte IL-1R2 protects heart from ischemia/reperfusion injury by attenuating IL-17RA-mediated cardiomyocyte apoptosis

Myocardial ischemia reperfusion (I/R) injury is a complex process with intense inflammatory response and cardiomyocyte apoptosis. As a decoy receptor of IL-1β, Interleukin-1 receptor type 2 (IL-1R2) inhibits IL-1β signaling. However, its role in I/R injury remains unknown. Here we found that the serum levels of IL-1R2 were significantly increased in patients with acute myocardial infarction (AMI) following interventional therapy. Similarly, after myocardial I/R surgery, IL-1R2 expression was significantly increased in heart of wild-type mice. In addition, IL-1R2-deficient mice heart showed enlarged infarct size, increased cardiomyocyte apoptosis together with reduced cardiac systolic function. Following exposure to hypoxia and reoxygenation (H/R), neonatal rat ventricular myocytes (NRVM) significantly increased IL-1R2 expression relying on NF-κB activation. Consistently, IL-1R2-deficient mice increased immune cells infiltrating into heart after surgery, which was relevant with cardiac damage. Additionally, IL-1R2 overexpression in cardiomyocyte protected cardiomyocyte against apoptosis through reducing the IL-17RA expression both in vivo and in vitro. Our results indicate that IL-1R2 protects cardiomyocytes from apoptosis, which provides a therapeutic approach to turn down myocardial I/R injury.

Cardiomyocyte IL-IR2 Protects Heart From Ischemia/Reperfusion Injury by Attenuating NLRP3 Inflammasome Activation and IL-17RA-Mediated Apoptosis

Background: Myocardial ischemia reperfusion (I/R) is characterized by a complex inflammatory response that stimulates the formation of inflammasome and production of Interleukin-1β (IL-1β). As a decoy receptor for IL-1β, the role of Interleukin-1 receptor type 2 (IL-1R2) in myocardial I/R injury is still unclear. Here, for the first time, we report the underlying mechanisms of IL-1R2 in protecting cardiomyocyte against I/R injury. Methods: Initially, the expression of IL-1R2 in myocardial I/R injury was determined by RT-PCR and western blot assays. IL-1R2-deficiency mice and AAV-9 virus carrying IL-1R2 under cTnT promoter were administrated to identify the protective role of IL-1R2 and RNA-sequencing was performed to explore the underlying mechanisms of IL-1R2 in myocardial I/R injury. Besides, neonatal rat ventricular myocytes (NRVM) were isolated to investigate the relationships of IL-1R2, NLRP3 inflammasome and Interleukin 17 receptor A (IL-17RA). Findings: We demonstrated that the expression of IL-1R2 in cardiomyocyte was induced by I/R injury both in vivo and in vitro. IL-1R2-deficient mice decreased cardiac systolic function, increased infarct size and cardiomyocyte apoptosis. Whereas, Overexpression of IL-1R2 in cardiomyocyte protected cardiomyocyte against I/R-induced cell death through reducing the NLRP3 inflammasome activation and IL-17RA expression both in vivo and in vitro. Interpretation: Collectively, the upregulation of IL-1R2 in cardiomyocyte provides therapeutic effects in protecting cardiomyocyte against cell death during myocardial I/R injury. Funding: Natural Key Research and Development Project of Zhejiang Province, China (2018C03015), National Key Research and Development Program of China (2016YFC1102203), Zhejiang Provincial Natural Science Foundation of China under Grant (LQ17H020002). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: The collection of blood plasma from AMI patients and healthy controls was conducted with approval from the Institutional Animal Care and Use Committee, and all animal studies were conducted with approval from the Medical Ethics Committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine.

Interleukin-1 family and serotonin transporter in first-episode, drug-naive major depressive disorder: A pilot study

Abnormalities of neuroinflammatory process and serotonergic system have been reported in major depressive disorder (MDD). However, most previous studies were performed in recurrent MDD and only a few studies explored the interaction of the two systems. This study examined both systems concurrently and their clinical relevance in first-episode drug-naive MDD. Thirty-four MDD patients and 34 age and gender matched healthy controls (HC) were recruited. Plasma concentrations of the cytokines of interleukin-1 (IL-1) family, including IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type 2 (IL-1R2) were measured using enzyme-linked immune-sorbent assays. The serotonin transporter (SERT) availability in midbrain, thalamus, caudate, and putamen was examined by single-photon emission computed tomography with 123I-ADAM. There were significantly lower concentrations of pro-inflammatory IL-1β and its inhibitor, IL-1R2 in MDD than HC. The SERT availability was at the same level between groups. A negative association between IL-1Ra concentration and the SERT availability in midbrain was observed in MDD but not in HC. Both IL-1β concentration and the SERT availability in caudate negatively correlated with depression severity and the effect of IL-1β was not moderated or mediated by the SERT. In conclusion, this study demonstrated the involvement of IL-1 family in the early stage of MDD, especially for IL-1β. SERT was not the main central target of altered IL-1β and these two systems might contribute to MDD by different mechanisms. The pathophysiology might be varied between early and recurrent MDD and tuning treatment strategies at different clinical stages might be needed.

LncRNA A2M-AS1 lessens the injury of cardiomyocytes caused by hypoxia and reoxygenation via regulating IL1R2.

Myocardial ischemia and reperfusion injury (MI/RI) is a complex pathophysiological process, which can lead to severe myocardial injury. The long noncoding RNA alpha-2-macroglobulin antisense RNA 1 (A2M-AS1) has been revealed to be abnormally expressed in MI, However, its function in MI and the potential mechanism are still unclear. To evaluate the functional role of A2M-AS1 in hypoxia/reoxygenation (H/R)-induced neonatal cardiomyocytes and its potential molecular mechanism. Dataset GSE66360 was obtained from GEO database for analyzing the RNA expression of A2M-AS1 and interleukin 1 receptor type 2 (IL1R2). KEGG pathway enrichment analysis of the genes that co-expressed with A2M-AS1 was performed. Human neonatal cardiomyocytes were subjected to H/R to construct in vitro models. QRT-PCR and Western blot were adopted to test the levels of mRNA and protein. The viability and apoptosis of cardiomyocytes were tested by CCK-8 and flow cytometry assays, respectively. The expression of A2M-AS1 was notably downregulated in H/R-treated cardiomyocytes. Overexpression of A2M-AS1 can notably enhance the cell viability of H/R-damaged cardiomyocytes, whereas knockdown of A2M-AS1 showed the opposite outcomes. Besides, a negative correlation was showed between A2M-AS1 and IL1R2 expression. In H/R-treated cardiomyocytes, overexpression of IL1R2 weakened the promoting proliferation and anti-apoptosis effects caused by overexpressing A2M-AS1, however, IL1R2-knockdown abolished the anti-proliferation and pro-apoptosis effects caused by silencing A2M-AS1. This study demonstrates the potential regulatory role of A2M-AS1/ IL1R2 axis in cardiomyocytes suffered from H/R, and provides insight into the protection of MI/RI.

IL1R2 Blockade Suppresses Breast Tumorigenesis and Progression by Impairing USP15-Dependent BMI1 Stability.

Breast tumor initiating cells (BTICs) with ALDH+CD24−CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin‐1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse‐free survival. High IL1R2 promotes BTIC self‐renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1β, as demonstrated by the fact that IL1β induces the release of IL1R2 intracellular domain (icd‐IL1R2) and icd‐IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self‐renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs.

The impact of genetic variants in IL1R2 on cervical cancer risk among Uygur females from China: A case-control study.

BackgroundDisordered inflammation and immune response is an acknowledged risk factor for cervical cancer development. Interleukin‐1 receptor type 2 (IL1R2) is a decoy receptor for IL‐1 cytokines and involved in host inflammatory and immune progression which could lead to the lesion and neoplasia of cervix. In this study, we aimed to evaluate the relationships between IL1R2 polymorphisms and cervical cancer risk in Uygur females from China.MethodsIn this case–control study, genotypes of six selected variants (rs11674595, rs4851527, rs719250, rs3218896, rs3218977, and rs2072472) distributed in IL1R2 were detected among 247 cervical cancer patients and 286 healthy controls with the usage of an Agena MassARRY method. Furthermore, Genetic models and haplotype analyses were conducted to estimate the associations of IL1R2 polymorphisms with cervical cancer risk.ResultsAfter statistical analyses, rs719250 (odd ratio [OR] = 1.436, 95% confidence interval [95% CI] = 1.079–1.911, p = 0.013) and rs3218896 (OR = 1.552, 95% CI = 1.080–2.229, p = 0.017) showed obvious evidence in correlation to cervical cancer susceptibility owing to the surviving significant differences between cases and controls in allele model. Genetic model analyses also revealed significant associations of rs719250 and rs3218896 with cervical cancer risk in the codominant model, the dominant model and the log‐additive model even after adjustment for age (p < 0.05). Moreover, haplotype “T/A” of rs11674595/rs4851527 (adjusted OR = 0.73, 95% CI = 0.54–0.98, p = 0.037) and “T/C” of rs719250/rs3218896 (adjusted OR = 1.61, 95% CI = 1.10–2.36, p = 0.015) exhibited protective and risky effects for Uygur individuals on cervical cancer development, respectively.ConclusionOur data first shed the new light on the associations of IL1R2 polymorphisms with cervical cancer susceptibility among Uygur females. These results are supposed to facilitate the tumorigenesis genetic research among Chinese minorities.

Correction: Phosphoproteomic analysis reveals Smad protein family activation following Rift Valley fever virus infection.

[This corrects the article DOI: 10.1371/journal.pone.0191983.].

Phosphoproteomic analysis reveals Smad protein family activation following Rift Valley fever virus infection.

Rift Valley fever virus (RVFV) infects both ruminants and humans leading to a wide variance of pathologies dependent on host background and age. Utilizing a targeted reverse phase protein array (RPPA) to define changes in signaling cascades after in vitro infection of human cells with virulent and attenuated RVFV strains, we observed high phosphorylation of Smad transcription factors. This evolutionarily conserved family is phosphorylated by and transduces the activation of TGF-β superfamily receptors. Moreover, we observed that phosphorylation of Smad proteins required active RVFV replication and loss of NSs impaired this activation, further corroborating the RPPA results. Gene promoter analysis of transcripts altered after RVFV infection identified 913 genes that contained a Smad-response element. Functional annotation of these potential Smad-regulated genes clustered in axonal guidance, hepatic fibrosis and cell signaling pathways involved in cellular adhesion/migration, calcium influx, and cytoskeletal reorganization. Furthermore, chromatin immunoprecipitation confirmed the presence of a Smad complex on the interleukin 1 receptor type 2 (IL1R2) promoter, which acts as a decoy receptor for IL-1 activation.

Identification of immune-related genes in gill cells of Japanese eels (Anguilla japonica) in adaptation to water salinity changes

The changes in ambient salinity influence ion and water homeostasis, hormones secretion, and immune response in fish gills. The physiological functions of hormones and ion transporters in the regulation of gill-osmoregulation have been widely studied, however the modulation of immune response under salinity changes is not determined. Using transcriptome sequencing, we obtained a comprehensive profile of osmo-responsive genes in gill cells of Japanese eel (Anguilla japonica). Herein, we applied bioinformatics analysis to identify the immune-related genes that were significantly higher expressed in gill pavement cells (PVCs) and mitochondrial-rich cells (MRCs) in freshwater (FW) than seawater (SW) adapted fish. We validated the data using the real-time qPCR, which showed a high correlation between the RNA-seq and real-time qPCR data. In addition, the immunohistochemistry results confirmed the changes of the expression of selected immune-related genes, including C-reactive protein (CRP) in PVCs, toll-like receptor 2 (TLR2) in MRCs and interleukin-1 receptor type 2 (IL-1R2) in both PVCs and MRCs. Collectively our results demonstrated that those immune-related genes respond to salinity changes, and might trigger related special signaling pathways and network. This study provides new insights into the impacts of ambient salinity changes on adaptive immune response in fish gill cells.

Lower levels of interleukin-1β gene expression are associated with impaired Langerhans' cell migration in aged human skin.

SummaryLangerhans’ cells (LC) play pivotal roles in skin immune responses, linking innate and adaptive immunity. In aged skin there are fewer LC and migration is impaired compared with young skin. These changes may contribute to declining skin immunity in the elderly, including increased skin infections and skin cancer. Interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) are mandatory signals for LC migration and previous studies suggest that IL‐1β signalling may be dysregulated in aged skin. Therefore, we sought to explore the mechanisms underlying these phenomena. In skin biopsies of photoprotected young (< 30 years) and aged (> 70 years) human skin ex vivo, we assessed the impact of trauma, and mandatory LC mobilizing signals on LC migration and gene expression. Biopsy‐related trauma induced LC migration from young epidermis, whereas in aged skin, migration was greatly reduced. Interleukin‐1β treatment restored LC migration in aged epidermis whereas TNF‐α was without effect. In uncultured, aged skin IL‐1β gene expression was lower compared with young skin; following culture, IL‐1β mRNA remained lower in aged skin under control and TNF‐α conditions but was elevated after culture with IL‐1β. Interleukin‐1 receptor type 2 (IL1R2) gene expression was significantly increased in aged, but not young skin, after cytokine treatment. Keratinocyte‐derived factors secreted from young and aged primary cells did not restore or inhibit LC migration from aged and young epidermis, respectively. These data suggest that in aged skin, IL‐1β signalling is diminished due to altered expression of IL1B and decoy receptor gene IL1R2.

Interleukin 1 receptor type 2 gene polymorphism is associated with reduced risk of preterm birth

Objective: Interleukin 1 receptor type 2 (IL1R2) regulates the inflammatory pathway that results in preterm delivery. We aim to investigate the impact of IL1R2 gene polymorphisms on the risk of preterm delivery.Method: A total of 664 women with spontaneous preterm and term deliveries were genotyped for IL1R2 gene polymorphisms (rs2072476A/G, rs2071008G/T, rs2072474C/T) using Sequenom MassARRAY platform.Results: Ethnic-specific analysis revealed a significant association between the G allele of IL1R2 rs2072476 polymorphism and reduced risk of PTB in the Indian ethnic subgroup (OR: 3.7, 95% CI: 1.3–11.3, p = 0.017). The odds of G allele occurring among Indian women with term delivery (>37 weeks) was three times higher than those with preterm delivery (<37 weeks). Genotype analysis showed a significant association between the GG genotype of IL1R2 rs2072476 polymorphism and term delivery in the Indian women.Conclusion: This study shows disparity in the occurrence of preterm birth due to the differences in the genotype of the women. Particularly, Indian women with the minor allele of IL1R2 rs2072476 polymorphisms were more likely to deliver at term (>37 weeks). These findings suggest the possible influence of maternal IL1R2 gene polymorphism on the risk of preterm delivery.

Fetal thymus graft enables recovery from age-related hearing loss and expansion of CD4-Positive T cells expressing IL-1 receptor type 2 and regulatory T Cells

BackgroundAccumulating evidence has indicated the relationship between the systemic immune system and the central nervous system including the inner ear.ResultsWe have shown that age-related developments of T-cell dysfunction, hearing loss, and degeneration of cochlear spiral ganglion (SG) neurons observed in 6-month-old mice were recovered in 12 months old mice which previously given fetal thymus transplants twice. We have also demonstrated that CD4+ T cells expressing interleukin 1 receptor type 2 (IL-1R2) and naturally occurring regulatory T cells (nTregs), which expanded in aged 12-month-old mice, were reduced in the thymus-grafted mice of the same age.ConclusionIt is conceivable that the rejuvenation of systemic immune function by fetal thymus grafts contributes not only to the activation of cellular immunity but also to the decrease of IL-1R2+ CD4+ T cells or nTregs, which cells accelerate both age-related hearing loss (AHL) and neurodegeneration of the cochlear neurons. Further studies on the interactions among IL-1R2 expression on CD4+ T cells, Tregs, and neuronal cells and also on the relationships between fetal thymus grafting and the rejuvenation of systemic immunity should be designed in order to advance towards therapeutic effects on neurosenescence, including AHL.

Epithelial IL-1R2 acts as a homeostatic regulator during remission of ulcerative colitis.

Ulcerative colitis (UC) is a chronic intestinal inflammatory disease that may undergo periods of activity followed by remission. We aimed to identify the endogenous regulatory mechanisms that may promote disease remission. Transcriptional and protein analysis of the intestinal mucosa revealed that the IL-1 decoy receptor, interleukin-1 receptor type 2 (IL1R2), was upregulated in remission compared with active UC and controls. We identified epithelial cells as being responsible for increased IL-1R2 production during remission. Expression of IL1R2 was negatively regulated by Wnt/beta-catenin signals in colonic crypts or epithelial stem cell cultures; accordingly, epithelial stem cells upregulated IL-1R2 upon differentiation. Blocking IL-1R2 in isolated colonic crypt cultures of UC patients in remission and T-cell cultures stimulated with biopsy supernatant from UC patients in remission boosted IL-1β-dependent production of inflammation-related cytokines. Finally, IL1R2 transcription was significantly lower in patients that relapsed during a 1-year follow-up period compared with those in endoscopic remission. Collectively, our results reveal that the IL-1/IL-1R2 axis is differentially regulated in the remitting intestinal mucosa of UC patients. We hypothesize that IL-1R2 in the presence of low concentrations of IL-1β may act locally as a regulator of intestinal homeostasis.