Role of Interleukin 1 Receptor 2 in Kidney Disease.

The interleukin 1 (IL-1) family plays a significant role in the innate immune response. IL-1 receptor 2 (IL-1R2) is the decoy receptor of IL-1. It is a negative regulator that can be subdivided into membrane-bound and soluble types. IL-1R2 plays a role in the IL-1 family mainly through the following mechanisms: formation of inactive signaling complexes upon binding to the receptor auxiliary protein and inhibition of ligand IL-1 maturation. This review covers the roles of IL-1R2 in kidney disorders. Chronic kidney disease, acute kidney injury, lupus nephritis, IgA nephropathy, renal clear cell carcinoma, rhabdoid tumor of kidney, kidney transplantation, and kidney infection were all shown to have abnormal IL-1R2 expression. IL-1R2 may be a potential marker and a promising therapeutic target for kidney disease.

Expression of interleukin-1ß and its receptor in human granulosa cells and their association with steroidogenesis.

This study aimed to investigate whether interleukin 1ß (IL-1ß) and soluble IL-1 receptor 2 (sIL-1R2) are expressed in human granulosa cells (GCs) and relate to ovarian steroidogenesis. Ninety-six women undergoing in vitro fertilization (IVF) were recruited. RT-PCR and immunocytochemistry were used to detect mRNAs and proteins of IL-1ß and IL-1R2, respectively. The steroidogenesis of primary cultured GCs was evaluated following treatment with either IL-1ß alone or IL-1ß and FSH in combination. There were positive correlations between serum IL-1ß and serum progesterone (r = 0.220, p = 0.032) and follicular fluid (FF) estradiol (r = 0.242, p = 0.018). Additionally, serum and FF sIL-1R2 were negatively and positively correlated with FF estradiol (r = -0.376, p = 0.005) and FF progesterone (r = 0.434, p = 0.001), respectively. The mRNA and protein expression of IL-1ß and IL-1R2 became evident in GCs. IL-1ß alone significantly increased estradiol secretion from GCs, but in the presence of FSH, it could notably promote progesterone secretion in addition to estradiol. In conclusion, IL-1ß and sIL-1R2 are expressed in human GCs and substantially contribute to ovarian steroidogenesis, suggesting that the IL-1ß system may be a potential target for optimizing ovarian hyperstimulation and steroidogenesis in IVF cycles.

Dendritic cell-derived IL-27 p28 regulates T cell program in pathogenicity and alleviates acute graft-versus-host disease.

Interleukin 27 (IL-27), a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28, is a pleiotropic cytokine with both pro-and anti-inflammatory properties. However, the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood. In this study, utilizing mice with IL-27 p28 deficiency in dendritic cells (DCs), we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses, corresponding to aggravated aGVHD in mice. In addition, using single-cell RNA sequencing, we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL-1R2+TIGIT+ pathogenic CD4+ T cells in the thymus at a steady state. Mechanistically, IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses, leading to the inhibition of Treg cell differentiation and function. Finally, patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28. Thus, our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development. IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.

Neutrophil-derived extracellular vesicles promote feed-forward inflammasome signaling in cystic fibrosis airways.

Cystic fibrosis (CF) airways feature high extracellular levels of the IL-1 family of proinflammatory mediators. These mediators are cleavage products of caspase-1, the final protease in the inflammasome cascade. Due to the proven chronic presence of reprogrammed neutrophils in the CF airway lumen, understanding inflammasome signaling in these cells is of great importance to understand how disease is perpetuated in this milieu. Here, we hypothesized that CF airway neutrophils contribute to chronic inflammation, in part, via the packaging of inflammasome-inducing signals in extracellular vesicles (EVs). We confirmed that CF airway fluid is enriched in IL-1α, IL-1ß, and IL-18, and that CF airway neutrophils up-regulate the activating receptor IL-1R1. Meanwhile, down-modulatory signals such as IL-1R2 and IL-1RA are unchanged. Active caspase-1 itself is present in CF airway fluid EVs, with neutrophil-derived EVs being most enriched. Using a transmigration model of CF airway inflammation, we show that CF airway fluid EVs are necessary and sufficient to induce primary granule exocytosis by naïve neutrophils (hallmark of reprogramming) and concomitantly activate caspase-1 and IL-1ß production by these cells and that the addition of triple-combination highly effective CFTR modulator therapy does not abrogate these effects. Finally, EVs from activated neutrophils can deliver active caspase-1 to primary tracheal epithelial cells and induce their release of IL-1α. These findings support the existence of a feed-forward inflammatory process by which reprogrammed CF airway neutrophils bypass 2-step control of inflammasome activation in neighboring cells (naïve neutrophils and epithelial cells) via the transfer of bioactive EVs.

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

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

Macrophage migration inhibitory factor regulates specific innate immune sensor responses in gingival epithelial cells.

BACKGROUND: The gingival epithelium protects periodontal tissues and the alveolar bone by maintaining a steady state of regulated inflammatory surveillance, also known as healthy homeostasis. Accordingly, the repertoire of receptors present within the gingival epithelium showcases its ability to recognize microbial colonization and contribute to bacterial sensing. Macrophage migration inhibitory factor (MIF) is one of many cytokines that are expressed in this protective state and is involved in neutrophil regulation. However, its role in the maintenance of healthy gingival tissue has not been described. METHODS: Gingival tissues from wild-type (WT) and Mif knock-out (KO) mice were stained for neutrophils and three key neutrophil chemoattractants: MIF, Gro-α/CXCL1, and Gro-ß/CXCL2 in the junctional epithelium (JE). In addition, gene silencing studies were performed using gingival epithelial cells (GECs) to examine the role of MIF on transcription of key bacterial recognition receptors Toll-like receptors (TLR)-1, -2, -4, -6, -9 and interleukin-1 receptors (IL-1R1 and IL-1R2) in response to oral bacterial stimulation. RESULTS: WT murine gingival tissues demonstrated high expression of MIF in the JE. In Mif KO mice, despite the significant reduction of Gro-α/CXCL1 and Gro-ß/CXCL2, there was a slight increase in neutrophils. Gene silencing experiments showed that MIF down-regulated the mRNA expression of TLR4, IL-1R1, and IL-1R2 in GEC, in addition to decreasing secreted IL-8/CXCL8 in response to bacteria. CONCLUSIONS: MIF regulates the expression of TLR4, IL-1Rs, and IL-8/CXCL8, components that are all involved in maintaining oral health. Our data demonstrate that MIF is a significant contributor to the maintenance of healthy oral homeostasis.

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-1ß, Interleukin-1 receptor type 2 (IL-1R2) inhibits IL-1ß 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.

In vitro effects of curcumin on proinflammatory cytokines and expression of their genes in minor salivary gland tissue of patients with Sjogren's syndrome.

Curcumin reduces disease severity and ameliorates lupus-like/Sjögren's Syndrome-like disease in mice model. The immunological basis of these effects is largely unknown. This study examined the effects of curcumin on pro-inflammatory cytokines secreted by minor salivary glands in patients with primary Sjögren's syndrome (pSS). Minor salivary gland (MSG) tissue samples were collected from patients undergoing biopsy for suspected pSS. The tissues were treated with phytohemagglutinin (PHA) alone as well as PHA with curcumin (30 µM) and cultured in RPMI 1640 medium for 48 h at 37 °C in CO2 incubator. After the incubation period, culture supernatant and tissues were stored in the freezer (-80 °C). IL-6 levels were measured in supernatant by ELISA kit. Gene expressions of pro-inflammatory cytokines, namely IL-6, IL-8, TNF-α, IL-1ß, IL-4, IL-10, IL-17, IL-21, and IFN-γ, were measured by qPCR. IL-6 secretion levels and gene expressions were compared statistically between groups by Student's t test. Forty-seven patients were screened. Eight patients satisfied ACR/EULAR criteria for pSS. Seven patients with absent glandular inflammation and negative serology constituted sicca controls. These 15 subjects were included in final analysis. In pSS group, but not in controls, median IL-6 levels in supernatant were less in curcumin-treated as compared to PHA-alone subset [5.5 (0.7-13.34) vs 18.3 (12-32) ng/ml; p = 0.0156]. mRNA expression levels of IL-6 were also lower in curcumin-treated samples as compared to PHA alone, when cases and controls were analyzed together as well as in cases alone (p = 0.0009 and p = 0.0078, respectively); however, mRNA expression of IL-1ß was lower in curcumin-treated samples as compared to PHA alone, only when cases and controls were analyzed together (p = 0.0215). There was no difference in other cytokine gene expression levels between the subsets under the in-vitro experimental conditions. In conclusion, curcumin reduced mRNA expression as well as secretion of IL-6 levels by salivary gland tissue of patients with pSS. Curcumin also suppressed PHA-induced mRNA expression levels of IL-6 and IL-1ß in MSG tissue of patients with pSS and controls when analyzed together as a combined group.

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.

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.

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.

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.

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.

Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors.

IL-1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL-1α and IL-1ß are translated as proforms that require cleavage for full cytokine activity and release, while IL-1α is reported to occur as an alternative plasma membrane-associated form on many cell types. However, the existence of cell surface IL-1α (csIL-1α) is contested, how IL-1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL-1α after ligation of TLRs. Pro-IL-1α tethers to the plasma membrane in part through IL-1R2 or via association with a glycosylphosphatidylinositol-anchored protein, and can be cleaved, activated, and released by proteases. csIL-1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN-γ, independent of expression level. We also reveal how prior csIL-1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent-associated secretory phenotype via csIL-1α, but rather via soluble IL-1α. We believe these data are important for determining the local or systemic context in which IL-1α can contribute to disease and/or physiological processes.

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.

Fatigue in patients with plaque-type psoriasis: lack of an association with plasma cytokines.

BACKGROUND: Fatigue is common in patients with psoriasis, and cytokines have been postulated to influence fatigue. OBJECTIVES: This case-control study explored the plasma levels of selected cytokines in patients with psoriasis and compared them with fatigue and other clinical factors. MATERIALS AND METHODS: Eighty-four patients with chronic plaque-type psoriasis and 84 age- and gender-matched healthy subjects were enrolled. Psoriasis severity was measured using the Psoriasis Area and Severity Index (PASI), and skin-related quality of life using the Dermatology Life Quality Index (DLQI). Fatigue was rated with the fatigue Visual Analogue Scale (fVAS). Plasma levels of interleukin (IL)-1ß, IL-1Rα, IL-1RII, IL-6, and IL-10 were measured by electrochemiluminescence sandwich immunoassay and ELISA. RESULTS: IL-1Rα and IL-6 median concentrations were significantly higher in patients than healthy subjects: 203 pg/mL (interquartile range: 150-274) versus 166 pg/mL (128-212), p=0.008 for IL-Rα, and 0.82 pg/mL (0.25-1.40) versus 0.50 pg/mL (0.25-0.91), p=0.009 for IL-6. IL-1ß, IL-1RII, and IL-10 concentrations did not differ between patients and healthy subjects. Higher levels of IL-1Rα and IL-6 were associated with increased body mass index (BMI), but not with disease activity. Cytokine concentrations were not associated with fatigue. CONCLUSION: These findings do not support an association between fatigue and blood concentrations of selected pro- and anti-inflammatory cytokines. The increased IL-1Rα and IL-6 levels associated with increased BMI are probably caused by release of adipokines from adipose tissue; of these, leptin, in particular, is known to be a strong inflammatory stimulator.

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.

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.

Follicular structures of cows with cystic ovarian disease present altered expression of cytokines.

Ovulation is considered an inflammatory, cytokine-mediated event. Cytokines, which are recognized as growth factors with immunoregulatory properties, are involved in many cellular processes at the ovarian level. In this sense, cytokines affect fertility and are involved in the development of different ovarian disorders such as bovine cystic ovarian disease (COD). Because it has been previously demonstrated that ovarian cells represent both sources and targets of cytokines, the aim of this study was to examine the expression of several cytokines, including IL-1ß, IL-1RA, IL-1RI, IL-1RII, IL-4 and IL-8, in ovarian follicular structures from cows with spontaneous COD. The protein expression of these cytokines was evaluated by immunohistochemistry. Additionally, IL-1ß, IL-4 and IL-8 concentrations in follicular fluid (FF) and serum were determined by enzyme-linked immunosorbent assay (ELISA). In granulosa and theca cells, IL-1RI, IL-1RII, IL-1RA and IL-4 expression levels were higher in cystic follicles than in the control dominant follicles. The serum and FF concentrations of IL-1ß and IL-4 showed no differences between groups, whereas IL-8 concentration was detected only in FF of cysts from cows with COD. The FF and serum concentrations of IL-1ß and IL-8 showed no significant differences, whereas IL-4 concentration was higher in FF than in serum in both the control and COD groups. These results evidenced an altered expression of cytokines in ovaries of cows with COD that could contribute to the pathogenesis of this disease.

Global Responses of Il-1ß-Primed 3D Tendon Constructs to Treatment with Pulsed Electromagnetic Fields.

Tendinopathy is accompanied by a cascade of inflammatory events promoting tendon degeneration. Among various cytokines, interleukin-1ß plays a central role in driving catabolic processes, ultimately resulting in the activation of matrix metalloproteinases and a diminished collagen synthesis, both of which promote tendon extracellular matrix degradation. Pulsed electromagnetic field (PEMF) therapy is often used for pain management, osteoarthritis, and delayed wound healing. In vitro PEMF treatment of tendon-derived cells was shown to modulate pro-inflammatory cytokines, potentially limiting their catabolic effects. However, our understanding of the underlying cellular and molecular mechanisms remains limited. We therefore investigated the transcriptome-wide responses of Il-1ß-primed rat Achilles tendon cell-derived 3D tendon-like constructs to high-energy PEMF treatment. RNASeq analysis and gene ontology assignment revealed various biological processes to be affected by PEMF, including extracellular matrix remodeling and negative regulation of apoptosis. Further, we show that members of the cytoprotective Il-6/gp130 family and the Il-1ß decoy receptor Il1r2 are positively regulated upon PEMF exposure. In conclusion, our results provide fundamental mechanistic insight into the cellular and molecular mode of action of PEMF on tendon cells and can help to optimize treatment protocols for the non-invasive therapy of tendinopathies.