Decreased Expression of EZH2 in Granulosa Cells Contributes to Endometriosis-Associated Infertility by Targeting IL-1R2.

The mechanism by which endometriosis, a common gynecological disease characterized by chronic pelvic pain and infertility, causes infertility remains elusive. Luteinized unruptured follicle syndrome, the most common type of ovulatory dysfunction, is a cause of endometriosis-associated infertility involving reduced numbers of retrieved and mature oocytes. Ovulation is controlled by luteinizing hormone and paracrine signals produced within the follicle microenvironment. Generally, interleukin (IL)-1ß is elevated in endometriosis follicular fluid, whereby it amplifies ovulation signals by activating extracellular-regulated kinase 1/2 and CCAAT/enhancer binding protein ß pathways. However, this amplification of ovulation by IL-1ß does not occur in patients with endometriosis. To illuminate the mechanism of ovulatory dysfunction in endometriosis, we analyzed the effect of oxidative stress and IL-1ß expression on endometriosis follicles. We found that oxidative stress decreased EZH2 expression and reduced H3K27Me3 levels in endometriosis ovarian granulosa cells (GCs). Selective Ezh2 depletion in mice ovarian GCs reduced fertility by disturbing cumulus-oocyte complex expansion and reducing epidermal growth factor-like factor expression. Gene expression and H3K27Me3 ChIP-sequencing (ChIP-Seq) of GCs revealed IL-1 receptor 2 (IL-1R2), a high-affinity IL-1ß-receptor that suppresses IL-1ß-mediated inflammatory cascades during ovulation, as a crucial target gene of the EZH2-H3K27Me3 axis. Moreover, IL-1ß addition did not restore ovulation upon Ezh2 knockdown, indicating a vital function of IL-1R2 in endometriosis. Thus, our findings show that reducing EZH2 and H3K27Me3 in GCs suppressed ovulatory signals by increasing IL-1R2 expression, which may ultimately contribute to endometriosis-associated infertility.

Influence of Sociodemographic Characteristics and Inflammation-Related Gene Variants on the Comfort Level of Caregivers of Patients With Head and Neck Cancer.

Background: Sociodemographic characteristics and inflammatory cytokines, such as interleukin (IL)-1ß, IL-1 cytokine receptor type 2 (IL1R2), IL-6, and triggering receptor expressed on myeloid cells like 2 (TREML2), may influence psychological disorders, including discomfort. Single-nucleotide variants (SNVs) determine individual differences for the modulation of cytokines and indicate that genetics may also influence the comfort levels. However, the relationship between sociodemographic characteristics, holistic comfort, and the roles played by IL1B rs16944, IL1R2 rs4141134, IL6 rs1800795, and TREML2 rs3747742 SNVs on the comfort levels of family caregivers (FCGs) of head and neck cancer (HNC) patients in palliative care (PC) is unknown. Thus, its investigation consisted in the aim of the present study. Methods: A questionnaire was applied to obtain sociodemographic information on 95 FCGs. The genotypes were identified using TaqMan assays. The Holistic Comfort Questionnaire for the Caregiver, which consists of 49 questions, was used to measure comfort levels. Differences between groups were assessed by the t test and linear regression. Results: Employed FCGs (p = .04), those youngest (p = .04), smokers (p = .04), and those with IL1R2 GA or AA genotypes (p = .03) presented lower comfort regarding the overall, environmental, sociocultural, and psychospiritual domains, respectively. Conclusions: Employment status, smoking habit, young age, and SNV IL1R2 rs4141134 could influence the comfort levels of FCGs of patients with HNC in PC.

Association of ITPKB, IL1R2 and COQ7 with Parkinson's disease in Taiwan.

BACKGROUND/PURPOSE: Genetic and environmental factors play significant roles in the pathogenesis of Parkinson's disease (PD). Recently, 17 novel risk loci of PD were identified in a meta-analysis of genome-wide association study (GWAS) in the European populations. In order to clarify if these risk loci are associated with PD in Taiwanese population, we conducted a case-control study including 14 of the novel risk loci and analyzed the genetic distribution and allele frequency. METHODS: A total of 2798 subjects were recruited in this study. Genotyping was performed in 672 PD patients and 609 healthy controls by using Mass ARRAY, and data of another 1517 healthy controls from Taiwan Biobank were also examined. RESULTS: Our results show that the dominant models of ITPKB rs4653767 (OR (95% CI) = 0.832 (0.699, 0.990), p = 0.038), IL1R2 rs34043159 (OR (95% CI) = 0.812 (0.665, 0.992), p = 0.041) and COQ7 rs11343 (OR (95% CI) = 0.304 (0.180, 0.512), p < 0.001) were associated with PD. In allelic analysis, the T allele of IL1R2 rs34043159 (OR (95% CI) = 0.873 (0.772, 0.987), p = 0.03) and T allele of COQ7 rs11343 (OR (95% CI) = 0.098 (0.040, 0.238), p < 0.001) showed lower risk of PD. After Bonferroni correction, only dominant model and T allele of COQ7 rs11343 showed significantly reduced the risk of PD. CONCLUSION: This study suggests that ITPKB, IL1R2 and COQ7 have influence on the risk of PD in Taiwan.

The association of genetic polymorphisms in interleukin-1 receptors type 1 and type 2 with sudden sensorineural hearing loss in a Taiwanese population: a case control study.

BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is a disease with an unknown etiology; damage to the auditory nerve from inflammation due to viral infection or vascular incidents has been implicated. According to several studies, cytokines, including interleukins, are associated with SSNHL in terms of serum expression and genetic polymorphisms. Interleukin-1 (IL-1) plays a key role in inflammation and may be associated with SSNHL. This study analyzed the association of single nucleotide polymorphisms (SNPs) of IL-1 receptor (IL-1R) genes with SSNHL in Taiwan. METHODS: We conducted a case-control study involving 401 patients with SSNHL and 730 healthy controls. Four SNPs (IL-1R type 1 gene [IL1R1] [rs3917225 and rs2234650] and IL-1R type 2 gene [IL1R2] [rs4141134 and rs2071008]) were selected. The genotypes were determined using the TaqMan assay. The Hardy-Weinberg equilibrium (HWE) was tested for each SNP, and genetic effects were evaluated. RESULTS: The TT genotype of rs2234650 had an adjusted odds ratio (OR) of 2.988 (95% confidence interval [95% CI] 1.27-6.82) (P = 0.012) compared with the CC genotype in patients with SSNHL. The SNP rs2234650 was associated with SSNHL in the recessive model (TT vs. CC + CT, P = 0.0206, OR = 2.681). The CT genotype of rs4141134 had an adjusted OR of 3.860 (95% CI 2.01-7.44; P < 0.0001) compared with the TT genotype, in patients with SSNHL. The SNP rs4141134 was associated with SSNHL under the dominant model (CC + CT vs. TT, P < 0.0001, OR = 4.087). CONCLUSION: These findings suggest that IL1R1 and IL1R2 gene polymorphisms may contribute to an increased risk of SSNHL in Taiwan.

Adipose-Derived Extract Suppresses IL-1ß-Induced Inflammatory Signaling Pathways in Human Chondrocytes and Ameliorates the Cartilage Destruction of Experimental Osteoarthritis in Rats.

We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1ß) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1ß combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1ß-induced inflammatory signaling pathway by upregulation of IL-1R2 expression.

Influence of IL1B (rs16944) and IL1R2 (rs4141134) polymorphisms on aggressiveness and prognosis of cutaneous melanoma.

Cutaneous melanoma is the most aggressive skin cancer with high mortality. Proinflammatory cytokines can modulate the proliferation and survival of cutaneous melanoma cells. Higher levels of interleukin-1ß (IL1B) were associated with tumor cell proliferation, invasion, and migration, and the IL-1 type II receptor (IL1R2) serves as an endogenous inhibitor of IL1B signaling. Single-nucleotide variations (SNVs) in these genes (IL1B rs16944 and IL1R2 rs4141134) can modulate cytokine production and binding; however, their role in cutaneous melanoma is still unknown. Thus, we investigated the influence of the above SNVs in clinicopathological aspects and cutaneous melanoma patients' survival. In the present study, we analyzed 193 patients with cutaneous melanoma for IL1B c.-598T>C (rs16944) and IL1R2 c.-2009G>A (rs4141134) genotypes with TaqMan assays. Differences between groups were calculated using χ2 or Fisher's exact test and multiple logistic regression. Progression-free survival (PFS) and melanoma-specific survival were calculated by Kaplan-Meier and Cox methods. The prognostic value of IL1R2 was also analyzed by the online consensus survival webserver for skin cutaneous melanoma (OSskcm). We found that IL1R2 rs4141134 GG genotype was more common in patients with nodular subtype (49.1% vs. 29.8%, P = 0.01) and the frequency of IL1R2 rs4141134 GG or GA was higher in patients with Clark levels III-V (87.4% vs. 75.8%, P = 0.04). Patients with IL1R2 rs4141134 GG or GA genotypes presented lower PFS (hazard ratio: 3.12, 95% confidence interval, 1.10-8.79, P = 0.03) when compared with AA genotype, supported by OSskcm results. Thus, our study presented for the first time preliminary evidence that IL1R2 rs4141134 SNV may modulate cutaneous melanoma clinicopathological aspects and survival possible by allowing IL1B signaling.

Potential role of a three-gene signature in predicting diagnosis in patients with myocardial infarction.

In this study, we evaluated the diagnostic value of key genes in myocardial infarction (MI) based on data from the Gene Expression Omnibus (GEO) database. We used data from GSE66360 to identify a set of significant differentially expressed genes (DEGs) between MI and healthy controls. Logistic regression, least absolute shrinkage and selection operator (LASSO) regression, support vector machine recursive feature elimination (SVM-RFE), and SignalP 3.0 server were used to identify the potential role of genes in predicting diagnosis in patients with MI. Principal component analysis (PCA), receiver operating characteristic (ROC) curve analyses, area under the curve (AUC) analyses, and C-index were used to estimate the diagnostic value of genes in patients with MI. The association was validated using six other independent data sets. Subsequently, bioinformatics analysis was conducted based on the aforementioned potential genes. A meta-analysis was performed to evaluate the diagnostic value of the genes in MI. Forty-four DEGs were selected from the GSE66360 dataset. A three-gene signature consisting of CCL20, IL1R2, and ITLN1 could effectively distinguish patients with MI. The three-gene signature was validated in seven independent cohorts. Functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to reveal the involvement of the three-gene signature in inflammation-related biological processes and pathways. Moreover, diagnostic meta-analysis results of the three-gene signature showed that the pooled sensitivity, specificity, and AUC for MI were 0.80, 0.90, and 0.93, respectively. These results suggest that the three-gene signature is a novel candidate biomarker for distinguishing MI from healthy controls.

Cytokine Signature of Dengue Patients at Different Severity of the Disease.

Clinical presentations of dengue fever (DF) are diverse and non-specific, causing unpredictable progression and outcomes. Its progression and severity have been associated with cytokine levels alteration. In this study, dengue patients were classified into groups following the 2009 WHO dengue classification scheme to investigate the cytokine signature at different severity of the disease: dengue without warning sign symptoms (A); dengue with warning signs (B); severe dengue (C); other fever (OF) and healthy (Healthy). We analyzed 23 different cytokines simultaneously, namely IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-33, CD14, CD54, CD62E, CD62L, CD62p, CD106, CD121b, CD154, CD178, GM-CSF, IFN-g, MIF, ST2 and TNF from patients admitted to National Cheng Kung University Hospital during the 2015 Taiwan dengue outbreak. Cytokines TNF, CD54, CD62E, CD62L, CD62P, GM-CSF, IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, INF-g and MIF were elevated while CD106, CD154, IL-4 and L-33 were decreased when compared to the control. IL-10 demonstrated to be a potential diagnostic marker for DF (H and A group; AUC = 0.944, H and OF group; AUC = 0.969). CD121b demonstrated to be predictive of the SD (A and B group; AUC = 0.744, B and C group; AUC = 0.775). Our results demonstrate the cytokine profile changes during the progression of dengue and highlight possible biomarkers for optimizing effective intervention strategies.

IL-1R2 expression in human gastric cancer and its clinical significance.

BACKGROUND: Interleukin-1 receptor type II (IL-1R2), also known as CD121b, is a member of the IL-1 receptor family. IL-1R2 acts as negative regulator of the IL-1 system, modulating IL-1 availability for the signaling receptor. IL-1R2 is abnormally expressed in many human inflammatory diseases and cancers, and has important clinical significance. The present study was designed to investigate IL-1R2 expression in human gastric cancer (GC) tissues and the associated clinical implications. METHODS: Immunohistochemistry was used to identify the clinical significance and prognostic value of IL-1R2 expression in GC tissues. We investigated IL-1R2 expression in GC tissues, cells, and serum using real-time PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) assays. RESULTS: IL-1R2 was highly expressed in GC tissues, and the overall survival in patients with advanced GC and high IL-1R2 expression was significantly poorer than that in patients with advanced GC and low IL-1R2 expression. Moreover, IL-1R2 mRNA levels in GC tissues and most GC cells were higher than those in para-cancer tissues and GES1 human gastric mucosal epithelial cells. The level of plasma-soluble IL-1R2 in GC patients was higher than that of the healthy control group. CONCLUSION: Increased IL-1R2 levels are involved in the initiation and progression of human GC, and IL-1R2 might be employed to develop immunotherapeutic approaches targeting GC.

Induction of the IL-1RII decoy receptor by NFAT/FOXP3 blocks IL-1ß-dependent response of Th17 cells.

Derived from a common precursor cell, the balance between Th17 and Treg cells must be maintained within immune system to prevent autoimmune diseases. IL-1ß-mediated IL-1 receptor (IL-1R) signaling is essential for Th17-cell biology. Fine-tuning of IL-1R signaling is controlled by two receptors, IL-1RI and IL-RII, IL-1R accessory protein, and IL-1R antagonist. We demonstrate that the decoy receptor, IL-1RII, is important for regulating IL-17 responses in TCR-stimulated CD4+ T cells expressing functional IL-1RI via limiting IL-1ß responsiveness. IL-1RII expression is regulated by NFAT via its interaction with Foxp3. The NFAT/FOXP3 complex binds to the IL-1RII promoter and is critical for its transcription. Additionally, IL-1RII expression is dysregulated in CD4+ T cells from patients with rheumatoid arthritis. Thus, differential expression of IL-1Rs on activated CD4+ T cells defines unique immunological features and a novel molecular mechanism underlies IL-1RII expression. These findings shed light on the modulatory effects of IL-1RII on Th17 responses.

Pathological matrix stiffness promotes cardiac fibroblast differentiation through the POU2F1 signaling pathway.

Cardiac fibroblast (CF) differentiation into myofibroblasts is a crucial cause of cardiac fibrosis, which increases in the extracellular matrix (ECM) stiffness. The increased stiffness further promotes CF differentiation and fibrosis. However, the molecular mechanism is still unclear. We used bioinformatics analysis to find new candidates that regulate the genes involved in stiffness-induced CF differentiation, and found that there were binding sites for the POU-domain transcription factor, POU2F1 (also known as Oct-1), in the promoters of 50 differentially expressed genes (DEGs) in CFs on the stiffer substrate. Immunofluorescent staining and Western blotting revealed that pathological stiffness upregulated POU2F1 expression and increased CF differentiation on polyacrylamide hydrogel substrates and in mouse myocardial infarction tissue. A chromatin immunoprecipitation assay showed that POU2F1 bound to the promoters of fibrosis repressors IL1R2, CD69, and TGIF2. The expression of these fibrosis repressors was inhibited on pathological substrate stiffness. Knockdown of POU2F1 upregulated these repressors and attenuated CF differentiation on pathological substrate stiffness (35 kPa). Whereas, overexpression of POU2F1 downregulated these repressors and enhanced CF differentiation. In conclusion, pathological stiffness upregulates the transcription factor POU2F1 to promote CF differentiation by inhibiting fibrosis repressors. Our work elucidated the crosstalk between CF differentiation and the ECM and provided a potential target for cardiac fibrosis treatment.

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

BACKGROUND: 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. OBJECTIVE: To evaluate the functional role of A2M-AS1 in hypoxia/reoxygenation (H/R)-induced neonatal cardiomyocytes and its potential molecular mechanism. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Association of ZNF184, IL1R2, LRRK2, ITPKB, and PARK16 with sporadic Parkinson's disease in Eastern China.

BACKGROUND: Genetic factors may play important roles in the pathogenesis of Parkinson's disease, and more than 40 loci involved in Parkinson's disease have been identified. Due to differing allele frequencies across origins, the associations of these loci and sporadic Parkinson's disease in the Eastern Chinese population are still unclear. OBJECTIVE: The aim of this study was to investigate the relationship between 20 single nucleotide polymorphisms and Parkinson's disease in the Eastern Chinese population. METHODS: A total of 441 Parkinson's disease patients and 384 healthy controls were recruited. The MassARRAY System was used to detect 20 single nucleotide polymorphisms. Odds ratios (OR) were calculated to assess the relationship between polymorphisms and Parkinson's disease susceptibility. RESULTS: We found that ITPKB rs4653767 (OR [95 % confidential interval (CI)] = 0.524 [0.309-0.922], p =  0.023), ZNF184 rs9468199 (OR [95 % CI] = 0.530 [0.326-0.862], p =  0.010), IL1R2 rs34043159 (OR [95 % CI] = 0.794 [0.651-0.968], p =  0.022), LRRK2 rs76904798 (OR [95 % CI] = 0.397 [0.225-0.700], p = 0.001), and PARK16 rs11240572 (OR [95 % CI] = 0.715 [0.531-0.962], p =  0.027) were significantly associated with Parkinson's disease. CONCLUSIONS: LRRK2 rs76904798, ZNF184 rs9468199, PARK16 rs11240572, ITPKB rs4653767, and IL1R2 rs34043159 may associate with Parkinson's disease in the Eastern Han Chinese population.

Platelet concentrate and type II IL-1 receptor are risk factors for allergic transfusion reactions in children.

PURPOSE: Allergic transfusion reactions (ATRs) are immunological reactions after transfusion. Interleukin-1 (IL-1) is a critical regulator for human diseases. We performed this study to investigate the association of type II IL-1 decoy receptor (IL1R2) expression with ATRs in children. METHODS: Children received blood transfusions between January and December 2019 were included. The age, sex, number and type of blood transfusion, allergic history, and medical history were collected and statistically analyzed. The blood samples were collected from children with and without ATRs for detecting the relative expression IL1R2 mRNA. Logistics regression analysis was performed to identify the risk factors for ATRs in children. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the predictive performance of risk factors. RESULTS: Totally, 28,840 transfusions in 20,230 children, with 236 ATRs (0.82%) in 117 patients (0.58%) were included. ATRs were common in children at the hematology-oncology department, in children received higher number of blood transfusions, and older children. Platelet concentrate induced a higher incidence of ATRs (3.31%) than red cell concentrate (0.22%, p < 0.0001). After the transfusion, IL1R2 mRNA level was higher in the blood samples in children with ATRs than those without ATRs (p < 0.0001). Logistics regression analysis indicated that platelet concentrate (95% CI 3.555, 293.782) and IL1R2 expression (95% CI 1.171 × 102, 1.494 × 104) were independent risk factors for ATRs in children. IL1R2 expression had high performance in predicting ATRs (AUC = 0.998, 100% sensitivity and 98.85% specificity). CONCLUSION: High IL1R2 expression level in children who received blood transfusions may predict the morbidity of ATR.

Paired box 6 inhibits cardiac fibroblast differentiation.

Cardiac fibroblast (CF) differentiation plays a crucial role in cardiac fibrosis, which is a specific manifestation distinguishing pathological cardiac hypertrophy from physiological hypertrophy. The DNA-binding activity of paired box 6 (Pax6) has been shown to be oppositely regulated in physiological and pathological hypertrophy; however, it remains unclear whether Pax6 is involved in CF differentiation during cardiac fibrosis. We found that Pax6 is expressed in the heart of and CFs isolated from adult mice. Moreover, angiotensin II (Ang II) induced the downregulation of Pax6 mRNA and protein expression in fibrotic heart tissue and cardiac myofibroblasts. Pax6 knockdown in CFs promoted the expression of the myofibroblast marker α-smooth muscle actin (α-SMA) and the synthesis of the extracellular matrix (ECM) proteins collagen I and fibronectin. Furthermore, we validated the ability of Pax6 to bind to the promoter regions of Cxcl10 and Il1r2 and the intronic region of Tgfb1. Pax6 knockdown in CFs decreased CXC chemokine 10 (CXCL10) and interleukin-1 receptor 2 (IL-1R2) expression and increased transforming growth factor ß1 (TGFß1) expression, mimicking the effects of Ang II. In conclusion, Pax6 exerts an inhibitory effect on CF differentiation and ECM synthesis by transcriptionally activating the expression of the anti-fibrotic factors CXCL10 and IL-1R2 and repressing the expression of the pro-fibrotic factor TGFß1. Therefore, maintaining Pax6 expression in CFs is essential for preventing CF differentiation, and provides a new therapeutic target for cardiac fibrosis.

Association of IL1R2 rs34043159 with sporadic Alzheimer's disease in southern Han Chinese.

BACKGROUND AND PURPOSE: The objective of the study was to investigate the relationship between IL1R2 rs34043159 and Alzheimer's disease (AD) in the Chinese population. METHODS: A total of 500 AD patients and 500 healthy controls were recruited. The SNaPshot technique was used to detect IL1R2 rs34043159. RESULTS: The dominant and recessive models of IL1R2 rs34043159 were associated with AD with or without adjustment of age, gender and education [dominant model, P = 0.019, odds ratio (OR) 1.42, 95% confidence interval (CI) 1.06-1.89, adjusted; recessive model, P = 0.011, OR 0.69, 95% CI 0.51-0.92, adjusted]. The recessive model of IL1R2 rs34043159 was associated with early-onset AD (EOAD) with or without adjustment of age, gender and education (recessive model, P = 0.038, OR 0.60, 95% CI 0.37-0.97, adjusted). The additive model was associated with late-onset AD (LOAD) (P = 0.041). The dominant model of IL1R2 rs34043159 was associated with LOAD with or without adjustment of age, gender and education (dominant model, P = 0.005, OR 1.68, 95% CI 1.17-2.44, adjusted). CONCLUSION: An association between the dominant and recessive model of IL1R2 rs34043159 and AD was found. The recessive model of IL1R2 rs34043159 was associated with EOAD. The additive and dominant models of IL1R2 rs34043159 were associated with LOAD.

The association of genetic polymorphisms in interleukin-1 receptors type 1 and type 2 with age-related hearing impairment in a Taiwanese population: a case control study.

BACKGROUND: Age-related hearing impairment (ARHI) is a major disability among the elder population. Chronic inflammation is an important factor in the development of ARHI. Interleukin-1 (IL-1) plays a key role in inflammation and may be associated with ARHI. The aim of this study is to analyze the associations of single nucleotide polymorphisms (SNPs) of IL-1 receptor genes with ARHI in an elderly population in Taiwan. METHOD: Participants ≥65 years of age were recruited for audiometric tests and genetic analyses. The bilateral pure-tone average (PTA) of high-tone hearing levels was calculated for ARHI evaluation. The associations of SNPs of the IL-1 receptor type 1 gene (IL1R1) (rs3917225 and rs2234650) and type 2 gene (IL1R2) (rs4141134 and rs2071008) with ARHI were analyzed in 182 ARHI-susceptible (case) and 176 ARHI-resistant (control) participants. RESULTS: The G allele of IL1R1 rs3917225 showed a decreased risk of ARHI after adjustments for sex, age, and noise exposure. The GG genotype of IL1R1 rs3917225 in all hereditary models and the TT genotype of IL1R2 rs2071008 in the recessive model also showed decreased risks of ARHI after adjustments. CONCLUSION: These findings suggest that IL1R1 and IL1R2 polymorphisms may contribute to the decreased risk of ARHI in the elderly population.

IL1R2 Polymorphisms are Associated with Increased Risk of Esophageal Cancer.

BACKGROUND: Esophageal cancer (EC) is the sixth leading cause of cancer death worldwide, and the overall incidence is increasing. OBJECTIVE: The aim of this study was to evaluate the association between single nucleotide polymorphisms in IL1R2 and EC risk in the Chinese population. METHODS: Genotyping of six SNPs of IL1R2 was performed with the Agena MassARRAY platform from 384 EC and 499 controls. The association between polymorphisms and EC risk was assessed by performing genetics models and haplotype analyses. RESULTS: Overall analysis results showed that the allele C of rs11674595 (odds ratio [OR] = 1.42, 95% confidence interval [CI]: 1.14-1.77, p = 0.002) and allele G of rs2072472 (allele: OR = 1.35, 95% CI: 1.08-1.69, p = 0.008) were associated with an increased EC risk. The rs11674595 and rs2072472 were found to be correlated with EC risk under the codominant, dominant, and additive models. Stratification analysis found that rs11674595 and rs2072472 were associated with increased EC risk in male and in age > 55 years old subgroup. In addition, Crs11674595Grs4851527 haplotype was significantly associated with 1.44-fold increased risk of EC (95% CI: 1.12-1.84, p = 0.004). CONCLUSION: Our results reveal the significant association between SNPs (rs11674595 and rs2072472) in the IL1R2 and EC risk in the Chinese Han population. The findings may provide meaningful reference for the prevention and treatment of EC.

Transcriptome Meta-Analysis Deciphers a Dysregulation in Immune Response-Associated Gene Signatures during Sepsis.

Sepsis is a life-threatening disease induced by a systemic inflammatory response, which leads to organ dysfunction and mortality. In sepsis, the host immune response is depressed and unable to cope with infection; no drug is currently available to treat this. The lungs are frequently the starting point for sepsis. This study aimed to identify potential genes for diagnostics and therapeutic purposes in sepsis by a comprehensive bioinformatics analysis. Our criteria are to unravel sepsis-associated signature genes from gene expression datasets. Differentially expressed genes (DEGs) were identified from samples of sepsis patients using a meta-analysis and then further subjected to functional enrichment and protein‒protein interaction (PPI) network analysis for examining their potential functions. Finally, the expression of the topmost upregulated genes (ARG1, IL1R2, ELANE, MMP9) was quantified by reverse transcriptase-PCR (RT-PCR), and myeloperoxidase (MPO) expression was confirmed by immunohistochemistry (IHC) staining in the lungs of a well-established sepsis mouse model. We found that all the four genes were upregulated in semiquantitative RT-PCR studies; however, MMP9 showed a nonsignificant increase in expression. MPO staining showed strong immunoreactivity in sepsis as compared to the control. This study demonstrates the role of significant and widespread immune activation (IL1R2, MMP9), along with oxidative stress (ARG1) and the recruitment of neutrophils, in sepsis (ELANE, MPO).

The Relationship Between Cytokine Production, CSF2RA, and IL1R2 Expression in Mammary Adenocarcinoma, Tumor Histopathological Parameters, and Lymph Node Metastasis.

OBJECTIVE: The aim of this study was to evaluate the relationship between cytokine production, GM-CSF receptor (CSF2RA), and IL-1 receptor (IL1R2) expression in mammary adenocarcinoma and their association with it histopathological parameters and lymph node metastasis. METHODS: We analyzed tumor biopsy samples (cultured in vitro) from 50 women (aged 43-75) with invasive ductal mammary adenocarcinomas. Enzyme-linked immunosorbent assay method the concentrations of interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 17, interleukin 18, interleukin 1ß, interleukin 1Ra, tumor necrosis factor α, interferon γ, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and vascular endothelial growth factor A were determined in culture supernatants. The expression of CSF2RA and IL1R2 in tumor biopsy was evaluated by immunohistochemical method. RESULTS: We showed that the "cytokine profile" of a tumor (the ability of tumor cells and its microenvironment to produce different cytokines) is very individual. It has been shown that the features of the cytokine profile of the mammary adenocarcinoma are important for the formation and realization of the metastatic potential of the mammary adenocarcinoma. We found correlations between some histopathological parameters of mammary adenocarcinoma and coefficients KGM-CSF/CSF2RA and KIL-1ß/IL1R2, which are the ratios of concentrations of granulocyte macrophage colony-stimulating factor and interleukin -1ß to expression of CSF2RA and IL1R2, respectively. KGM-CSF/CSF2RA positively correlated with highly differentiated cells, and KIL-1ß/IL1R2 positively correlated with the number of mitoses, poorly differentiated cells, and a number of lymph nodes with metastases. KGM-CSF/CSF2RA positively correlated with the concentrations of interleukin 6, interleukin 8, interleukin 1Ra, and granulocyte colony-stimulating factor. KIL-1ß/IL1R2 positively correlated with concentrations of interleukin 1ß and interferon γ and negative correlated with the concentrations of vascular endothelial growth factor A and tumor necrosis factor α. It is shown that KIL-1ß/IL1R2 can be considered as a prognostic indicator predicting the probability of mammary adenocarcinoma metastasis to regional lymph nodes. CONCLUSIONS: The ratios of granulocyte macrophage colony-stimulating factor and interleukin 1ß cytokines, produced in tumor, to the expression of CSF2RA and IL1R2 depend on levels of interleukin 6, interleukin 8, tumor necrosis factor α, interferon γ, granulocyte colony-stimulating factor, and vascular endothelial growth factor A and are important factors affecting the progression and metastasis of the breast cancer.