Interleukin-23 Receptor Gene Research Articles

Interleukin-23 receptor gene polymorphisms in Iranian patients with juvenile systemic lupus erythematosus

Introduction and objectivesConsidering the possible roles of interleukin-23 receptor (IL-23R) gene in the pathogenesis of juvenile systemic lupus erythematosus (JSLE), the objective of this study was to elucidate whether polymorphisms of the IL23R are associated with susceptibility to JSLE in an Iranian population. Materials and methodsA case-control study on 62 patients with JSLE and 78 healthy controls was performed to investigate the associations of four single nucleotide polymorphisms (SNPs) in IL-23R gene, namely, rs7517847, rs10489629, rs11209026, and rs1343151, with susceptibility to JSLE, using real-time polymerase chain reaction Taqman genotyping technique. ResultsAnalysis of allele and genotype frequency of four selected SNPs revealed statistically significant positive association between homozygous variant of rs7517847 (TT) (P, 0.02) and T allele at the same position (P, 0.01) with JSLE vulnerability. There was no significant association between other evaluated SNPs and JSLE susceptibility. ConclusionThese findings suggest that particular IL-23R gene variants could affect individual susceptibility to JSLE.

The association between genetic polymorphisms of interleukin 23 receptor gene and the risk of rheumatoid arthritis: An updated meta-analysis

This meta-analysis was conducted to confirm whether seven single nucleotide polymorphisms (SNPs) of interleukin-23 receptor (IL23R) gene are associated with rheumatoid arthritis (RA) susceptibility. RevMan version 5.3 was used to calculate statistical data. Sixteen articles involving 11,816 RA patients and 14,268 healthy controls were included in this meta-analysis. A significant association was identified between the rs11209026 polymorphism and RA susceptibility in Caucasians (AA vs. GG: OR = 1.78, 95% CI = 1.02–3.10, P = .04; AA vs. AG + GG: OR = 1.77, 95% CI = 1.02–3.08, P = .04). Additionally, our result showed that the G allele of IL23R/rs10489629 had a significantly increased frequency in RA patients of Caucasians and Asians (A vs. G: OR = 0.92, 95% CI = 0.88–0.97, P = .002; OR = 0.62, 95% CI = 0.44–0.87, P = .006, respectively). Furthermore, the meta-analysis revealed a significant association between the rs1343151 polymorphism and RA susceptibility in Caucasians (C vs. T: OR = 0.91, 95% CI = 0.87–0.96, P = .0004). Our meta-analysis confirmed the IL23R gene might be treated as a susceptible factor for RA.

Rs1884444 variant in IL23R gene is associated with a decreased risk in esophageal cancer in Chinese population.

Single nucleotide polymorphisms (SNPs) in interleukin-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. IL23R gene is still controversial in the study of esophageal cancer. The aim of this research is to investigate the influence of IL23R SNPs on the risk of esophageal cancer. Five hundred six esophageal cancer and 507 controls frequency matched by age and gender were conducted, and the genotypes were determined by the Agena MassARRAY. Logistic regression analysis was used to evaluate the odd ratios (ORs) and 95% confidence intervals (CIs) of rs1884444 and rs6682925 with susceptibility of esophageal cancer. A total of 30 articles are eligible. Pooled ORs and the 95% CI were calculated using the random-effect model. Database predicts the expression of IL23R gene in esophageal cancer. IL23R rs1884444 allele G decreased the risk of esophageal cancer under allele, genotype, and additive models (allele model: OR = 0.82, 95% CI: 0.68-0.98, P = .032; genotype model: OR = 0.65, 95% CI: 0.44-0.97, P = .035; additive model: OR = 0.82, 95% CI: 0.68-0.98, P = .031). Meta-analysis shown that IL23R rs1884444 increased the risk of overall disease in allele model (OR = 1.16, 95% CI: 1.08-1.25, P < .001), and also increased the risk of gastrointestinal tumor (OR = 1.18, 95% CI: 1.05-1.31, P = .005). The database analysis showed that the expression of IL23R gene was upregulated in esophageal cancer tissues. IL23R rs1884444 may play an important role in the susceptibility of esophageal cancer.

TUNICAMYCIN-INDUCED ENDOPLASMIC RETICULUM STRESS UP-REGULATES TUMOUR-PROMOTING CYTOKINES IN ORAL SQUAMOUS CELL CARCINOMA

Objectives Signal transducer and activator of transcription (STAT)-3 lies at the convergence point of key pathways involved in many malignancies including oral squamous cell carcinoma (OSCC). Endoplasmic reticulum stress (ERS) and the unfolded protein response promote either survival or apoptosis in different cancers. We investigated the expression of STAT3 pathway-related genes and proteins under ERS in OSCC. Three normal oral keratinocyte (NOK) and three OSCC cell lines were subjected to tunicamycin to induce ERS for 24 hours or to the vehicle medium as control. A pathway-focussed array was used to analyse the modulation of STAT3 pathway gene expression under ERS using qPCR. The expression of key regulated proteins was investigated in the cell lines using immunocytochemistry and in 76 OSCC and 9 normal oral mucosa (NOM) tissue samples using tissue microarray technology and immunohistochemistry. Findings ERS resulted in up-regulation of interleukin-6 receptor (IL6R) gene in NOK cell lines (p = 0.001) and IL5 (p = 0.005) and IL22 (p = 0.024) in OSCC cell lines. Greater STAT3 (p = 0.019) and leukaemia inhibitory factor receptor (p = 0.042) protein expression was observed in treated than untreated NOK cell lines. Conclusions The gene and protein regulation patterns show that ERS plays a role in modifying the tumour microenvironment in OSCC by up-regulating tumour-promoting cytokines.

Relationship between IL-23R gene polymorphism and susceptibility to acute coronary syndrome

Objective To investigate the relationship between the rs6682925T/C gene polymorphism of interleukin (IL)-23 receptor (IL-23R) gene and susceptibility to acute coronary syndrome (ACS). Methods A case-control study. 180 ACS patients (the disease group) and 90 patients with normal coronary angiography(control group) were selected from January 2017 to April 2018 in jingzhou central hospital. The disease group included 109 males and 71 females,aged (59.95±9.29) years old and the control group included 49 males and 41 females, aged (58.39±9.43) years old. The gene polymorphism of IL-23R gene rs6682925T/C was detected by Sanger sequencing,and serum IL-23R concentration in peripheral blood was detected by ELISA. The statistical analysis methods used include normal distribution test,t test,analysis of variance and chi-square (χ2) test. Unconditional logistic regression analysis of the relationship between IL-23R gene rs6682925T/C polymorphism and susceptibility to ACS. Results There were no significant differences in gender, age, body mass index, apolipoprotein b, total cholesterol and low-density lipoprotein cholesterol between the ACS group and the control group(χ2=0.923, P>0.05; t=1.294, P>0.05; t=-0.574, P>0.05; t=-0.417, P>0.05). However, the differences in triglyceride, fasting blood glucose, high-density lipoprotein cholesterol,smoking rate,diabetes and hypertension were statistically significant(t=5.411, P<0.05; t=5.828, P<0.05; t=-6.655, P<0.05; χ2=7.738, P<0.05; χ2=13.201, P<0.05; χ2=8.359, P<0.05). Compared with the control group, the IL-23R rs6682925 polymorphic site in ACS group had significant differences in the distribution of TT, CT, CC genotype and C allele frequency (χ2=9.858, P<0.05; χ2=10.833, P<0.05) and the frequency of C allele in the acute coronary syndrome group was significantly higher than that of the control group. In addition, the risk of rs6682925 CC genotype carriers suffer from acute coronary syndrome was 3.261 times that of TT genotype (95% CI:1.553-6.847,P=0.002). Compared with the control group,the serum IL-23R concentration in the peripheral blood of the ACS group was significantly increased [(353.20±140.79) pg/ml vs (187.41±123.36) pg/ml,t=9.495,P<0.01]. Conclusions IL-23R rs6682925 gene polymorphism is associated with genetic susceptibility to ACS,and the rs6682925 CC genotype might act as a risk factor for ACS. Key words: Interleukin-23 receptor; Single nucleotide polymorphism; Acute coronary syndrome; Disease susceptibility

Interleukin-23 receptor (IL-23R) gene polymorphisms and haplotypes associated with the risk of preeclampsia: evidence from cross-sectional and in silico studies.

Pre-eclampsia is a relatively common pregnancy disorder. Serum concentrations of certain pro-inflammatory molecules and cytokines like interleukin-23 may affect the pathogenesis of pre-eclampsia. The interleukin-23 receptor (IL-23R) gene plays an important role in the progression of inflammatory and autoimmune diseases and IL-23 polymorphisms might influence the susceptibility of pre-eclampsia. The aim of the recent study was to establish the association between IL-23R gene polymorphisms and the susceptibility for developing of pre-eclampsia. One hundred and fifty-eight pregnant patients with pre-eclampsia and 153 controls were genotyped using RFLP-PCR and AS-PCR. Also, an in silico analysis was performed to predict possible effects of these variations on IL-23R mRNA and protein structures. The frequency of the AG genotype of rs11209026 is related to a higher risk of pre-eclampsia. The mutant C and A allele in rs10889677 and rs11209026 SNPs, respectively, are correlated with the risk of pre-eclampsia and they are more frequent in severe late onset PE. We found higher frequency of the haplotype CG in patients with pre-eclampsia in comparison to healthy controls, as well as, the CG haplotype frequency significantly increased the risk of PE in severe, early onset, and late onset sub-groups. The results of computational analysis predicted rs11209026 and rs10889677 SNPs as functional variations, which can influence IL-23R mRNA and protein. The results of present study show positive association between polymorphisms in the IL-23R gene and pre-eclampsia. Therefore, the presence of IL-23R rs11209026, rs10889677 polymorphism might be markers for the genetic susceptibility to pre-eclampsia.

Erythropoietin inhibits SGK1-dependent TH17 induction and TH17-dependent kidney disease.

IL-17-producing CD4+ cells (TH17) are pathogenically linked to autoimmunity including to autoimmune kidney disease. Erythropoietin's (EPO) newly recognized immunoregulatory functions and its predominant intra-renal source suggested that EPO physiologically regulates TH17 differentiation, thereby serving as a barrier to the development of autoimmune kidney disease. Using in vitro studies of human and murine cells and in vivo models, we show that EPO ligation of its receptor (EPO-R) on CD4+ T cells directly inhibits TH17 generation and promotes trans-differentiation of TH17 into IL-17-FOXP3+CD4+ T cells. Mechanistically, EPO/EPO-R ligation abrogates upregulation of SGK1 gene expression and blocks p38 activity to prevent SGK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL-17 and IL-23 receptor genes. In a murine model of TH17-dependent aristolochic acid (ArA)-induced, interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits TH17 formation and clinical/histological disease expression. EPO/EPO-R ligations on CD4+ T cells abrogate, while absence of T cell-expressed EPO-R augments, TH17 induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and TH17 generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulate TH17 cells to limit expression of TH17-associated autoimmune kidney disease.

Tunicamycin-induced endoplasmic reticulum stress up-regulates tumour-promoting cytokines in oral squamous cell carcinoma

AimsSignal transducer and activator of transcription (STAT)-3 lies at the convergence point of key pathways involved in many malignancies including oral squamous cell carcinoma (OSCC). Endoplasmic reticulum stress (ERS) and the unfolded protein response have been shown to be involved in the pathogenesis and progression of different cancers by influencing key cellular processes such as apoptosis. We investigated the differential expression of STAT3 pathway-related genes and proteins under ERS in OSCC. MethodsThree normal oral keratinocyte (NOK) and three OSCC cell lines were subjected to tunicamycin to induce ERS for 24 h or to the vehicle medium as control. A pathway-focussed array was used to analyse the modulation of STAT3 pathway gene expression under ERS using qPCR. The expression of key regulated proteins was investigated in the cell lines using immunocytochemistry and in 76 OSCC and 9 normal oral mucosa (NOM) tissue samples using tissue microarray technology and immunohistochemistry. ResultsERS resulted in up-regulation of interleukin-6 receptor (IL6R) gene in NOK cell lines (p = 0.001) and IL5 (p = 0.005) and IL22 (p = 0.024) in OSCC cell lines. Greater STAT3 (p = 0.019) and leukaemia inhibitory factor receptor (p = 0.042) protein expression was observed in treated than untreated NOK cell lines. ConclusionsThe gene and protein regulation patterns show that ERS plays a role in modifying the tumour microenvironment in OSCC by up-regulating tumour-promoting cytokines.

Are genetic variations in IL-21-IL-23R-IL-17A cytokine axis involved in a pathogenic pathway of rheumatoid arthritis? Bayesian hierarchical meta-analysis.

Inflammatory cytokines have been established to be involved in the pathogenesis of rheumatoid arthritis (RA). The genetic polymorphisms in the interleukin (IL) 23 receptor (IL23R), IL21, and IL17 have been associated with RA risk. However, there is no conclusive understanding of the genes encoding the immunoinflammatory IL-21-IL-23R-IL-17A pathway in RA aetiopathogenesis. This meta-analysis was conducted to attain this goal. A comprehensive literature search was conducted in Scopus and PubMed to look for the relevant case-control studies up until 2018. A Bayesian hierarchical meta-analysis was carried out to assess the association between the polymorphisms and the risk of RA. The association was estimated by calculating the logarithm of odds ratio (Log OR) and 95% credible interval (95% CI). In this meta-analysis, 37 case-control studies comprising 23,506 RA patients and 25,984 healthy individuals were found for analyzing the IL23R, IL21, and IL1A gene polymorphism and risk of RA. In the IL23R gene rs1343151 SNP, the minor A allele significantly increased the risk of RA (Log OR = 0.085, 95% CI = 0.008, 0.156). Moreover, the minor AA genotype was significantly associated with increased RA risk (Log OR = 0.176, 95% CI = 0.028, 0.321). In addition, the C allele of the IL23R gene rs2201841 SNP significantly decreased the disease risk (Log OR = -0.544, 95% CI = -1.0, -0.065). Since Bayesian meta-analysis is a powerful strategy to pool the data, it can be mentioned that genetic polymorphisms of IL23R, but not IL21 and IL17A, are involved in susceptibility to RA.

Associations between IL-23R gene polymorphisms and the susceptibility of rheumatoid arthritis: a meta-analysis

Objective: This meta-analysis was aimed to verify the influences of interleukin 23 receptor (IL-23R) rs11209026 and rs2201841 polymorphisms on the susceptibility of rheumatoid arthritis (RA).Methods: We searched potentially relevant studies on the relationships of IL-23R gene rs11209026 and rs2201841 polymorphisms with RA susceptibility from PubMed (Medline), CNKI and EMBASE web databases. Crude odds ratios (ORs) along with 95% confidence intervals (95% CIs) were calculated to assess the strength of association through the fixed- or random-effects model.Results: Eight published articles containing 5544 RA patients and 5532 health individuals were included in our meta-analysis. In total analysis, we found IL-23R gene rs11209026 polymorphism was not related to RA susceptibility in all genetic models, but there was a significant association between rs2201841 polymorphism and RA susceptibility under G vs. A model. In stratified analysis by ethnicity, an increased RA susceptibility was detected for rs2201841 polymorphism in Caucasian group.Conclusion: The results of meta-analysis indicated that IL-23R gene rs2201841 polymorphism might be a susceptible factor for RA under G vs. A model, especially in Caucasian population.

GENE POLYMORPHISM;

Introduction: Reduced bone density in postmenopausal women is a complex disease with a strong genetic association. Causative factors are both acquired and genetic. Single nucleotide polymorphisms may be associated with genetic predisposition of this condition. Objectives: The purpose of this study is to find out an association between single nucleotide polymorphism (rs4845617) of IL-6R (Interleukin 6 receptor) gene and reduced bone density in cases of postmenopausal women and controls. Study Design: It is a retrospective case-control study. Duration: From March 2017 to Nov 2017. Setting: Different hospitals of Sargodha. Material and Method: About 30 blood samples were collected from postmenopausal women affected with reduced bone density and 30 healthy age-and gender-matched controls. All the blood samples underwent DNA extraction, Polymerase chain reaction and DNA sequencing techniques. Result: In this study, post menopausal women were screened for the rs4845617 in IL-6R gene for their association with reduced bone density. The chi-square test of independence showed that G allele of rs4845617 was significantly associated with reduced bone density in postmenopausal women (OR=2.28, χ2=8.98, p=0.002). Conclusion: Our results signify that this polymorphism may play a role in reduced bone density susceptibility in postmenopausal women.

Prognostic role of genetic polymorphisms of the interleukin-6 signaling pathway in patients with severe heart failure.

Heart failure (HF) is associated with perturbations of the interleukin-6 (IL-6) signaling pathway. A total of 559 Danish subjects with severe chronic HF enrolled in the previously reported Echocardiography and Heart Outcome Study were genotyped for three SNPs in IL6, nine in the IL-6 receptor gene (IL6R), and two in the IL-6 signal transducer gene (IL6ST). After a mean follow-up of 5.0 years, 5 SNPs in IL6R introns (rs12083537, rs6684439, rs4845622, rs4537545, and rs7529229) and a SNP in the IL6R coding region (rs2228145, also known as Asp358Ala) were associated with adverse outcomes, e.g., hazard ratios (HRs) for cardiovascular death and all-cause death 1.38 (CI: 1.09-1.76; P = 0.008) and 1.37 (CI: 1.10-1.70; P = 0.004) for rs6684439 heterozygotes, and 1.39 (CI: 1.09-1.77; P = 0.007) and 1.37 (CI: 1.10-1.70; P = 0.005) for rs4845622 heterozygotes, respectively. We conclude that SNPs in the IL-6 signaling pathway may be independent predictors of fatal outcomes in patients with severe HF.

IL-10 signaling in dendritic cells is required for tolerance induction in a murine model of allergic airway inflammation.

Allergen specific tolerance induction efficiently ameliorates subsequent allergen induced inflammatory responses. The underlying regulatory mechanisms have been attributed mainly to interleukin (IL)-10 produced by diverse hematopoietic cells, while targets of IL-10 in allergen specific tolerance induction have not yet been well defined. Here, we investigate potential cellular targets of IL-10 in allergen specific tolerance induction using mice with a cell type specific inactivation of the IL-10 receptor gene. Allergic airway inflammation was effectively prevented by tolerance induction in mice with IL-10 receptor (IL-10R) deficiency in T or B cells. Similarly, IL-10R on monocytes/macrophages and/or neutrophils was not required for tolerance induction. In contrast, tolerance induction was impaired in mice that lack IL-10R on dendritic cells: those mice developed an allergic response characterized by a pronounced neutrophilic lung infiltration, which was not ameliorated by tolerogenic treatment. In conclusion, our results show that allergen specific tolerance can be effectively induced without a direct impact of IL-10 on cells of the adaptive immune system, and highlight dendritic cells, but not macrophages nor neutrophils, as the main target of IL-10 during tolerance induction.

Role of Interleukin17F (IL17F) Gene Polymorphism in Susceptibility to Acute Myeloid Leukemia

Th17 cells (subset of CD4+ cells) are characterized by interleukin (IL)-17A and IL-17F production, which share strong homology, and surface expression of the IL-23 receptor (IL-23R). They have been implicated in the pathogenesis of inflammatory, autoimmune diseases and in many different types of human tumors, including lymphoma and myeloma. Objectives: The aim of this study was to determine the association between the polymorphic features located within the IL-17A, IL-17F and IL-23R genes and susceptibility to or association with AML and the relationship between these polymorphic variants and the plasma IL-17 levels in all studied groups. Subjects and Methods: 82 individual of Egyptian population including 27 AML patients, 40 individual who are relatives of those patients and 15 apparently healthy controls. All were subjected to detection of Interleukin 17F gene polymorphism by 2 steps: first Conventional Polymerase Chain Reaction then Restriction Fragment length Polymorphism by Restriction enzymeHIN1II (NLAIII) (PCR-RFLP) assay, Detection of Interleukin 17A and Interleukin23 receptor genetic polymorphisms by real time Polymerase Chain Reaction and Quantification of Interleukin 17 gene protein product by Enzyme Linked Immunosorbent Assay (ELISA). Results: our results revealed that the (G) variant of IL17F and its homozygosity were significantly higher among patients compared to relatives and healthy individual. While IL17-A and IL23-R polymorphisms elicit non statistical significant difference among the three groups. Also a significant correlation was observed between IL17 protein plasma level and the three polymorphisms (IL17F, IL17A and IL23R genetic polymorphisms). Conclusions: IL-17F gene G single mutant and GG homozygous mutant were associated with acute myeloid leukemia susceptibility in Egyptian population while IL17-A and IL23-R polymorphisms were not associated with susceptibility to the disease. Also there were statistical significant association (P˂0.05) and high statistical significant (P˂0.001) association between ELISA (IL17 plasma level) results and the three genetic polymorphisms in studied groups. There was high statistical significant difference (P˂0.001) between patients and other two groups in IL17 plasma level by ELISA.

Research Article Genetic polymorphism at Interleukin-7 receptor gene at +510 position and its impact on pain and other symptoms among HIV and AIDS patients

Research Article Genetic polymorphism at Interleukin-7 receptor gene at +510 position and its impact on pain and other symptoms among HIV and AIDS patients

Genetic Association between Interleukin-4 Receptor Polymorphisms and Cancer Susceptibility: A Meta-Analysis Based on 53 Case-Control Studies.

Polymorphisms in interleukin-4 receptor (IL-4R) gene have been reported susceptible to a variety of cancer types, nevertheless, data from these publications remained inconsistent and controversial. We further performed a comprehensive meta-analysis to present a precise estimation of its relationship. Extensive retrieve was performed in PubMed, Google Scholar and Web of Science up to May 25, 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were conducted to evaluate the overall strength of the associations in five genetic models, as well as in subgroup analyses, stratified by ethnicity, cancer type or source of control. Q-test, Egger's test and Begg's funnel plot were applied to evaluate the heterogeneity and publication bias. In-silico analysis was managed to demonstrate the relationship of IL-4R expression correlated with cancer tissues. Finally, 31 publications including 53 case-control studies were enrolled, with 24,452 cases and 24,971 controls. After a comprehensive analysis, no significant evidence was revealed for the association between four IL-4R polymorphisms (rs1801275, rs1805010, rs1805015, rs2057768) and cancer susceptibility in the overall population, as well as the subgroup analysis stratified by ethnicity, cancer type, the genotyping method or the source of control. To sum up, no evidence was identified between IL-4R polymorphisms and overall cancer susceptibility. Further well-designed studies with large sample sizes will be continued on this issue of interest.

Research Article Polymorphisms rs1800795 of interleukin-6 and rs2228145 of interleukin-6 receptor genes in Euro-Brazilians with adult-onset type 1 diabetes mellitus

Research Article Polymorphisms rs1800795 of interleukin-6 and rs2228145 of interleukin-6 receptor genes in Euro-Brazilians with adult-onset type 1 diabetes mellitus

Genetic Modulation of Adenosine-to-Inosine RNA Editing Selectively Disrupts Inflammasome and Extracellular Matrix Genes in Multiple Myeloma

IntroductionAs the second most common blood cancer in the U.S., multiple myeloma (MM) is typified by clonal plasma cell proliferation in the bone marrow (BM) and may progress to therapy-resistant plasma cell leukemia (PCL). Despite many novel therapies, relapse rates remain high as a result of malignant regeneration (self-renewal) of MM cells in inflammatory microenvironments. In addition to recurrent DNA mutations and epigenetic deregulation, inflammatory cytokine-responsive adenosine deaminase associated with RNA (ADAR1) mediated adenosine to inosine (A-to-I) RNA editing has emerged as a key driver of cancer relapse and progression. In MM, copy number amplification of chromosome 1q21, which contains both ADAR1 and interleukin-6 receptor (IL-6R) gene loci, portends a poor prognosis. Thus, we hypothesized that ADAR1 copy number amplification combined with inflammatory cytokine activation of ADAR1 stimulate malignant regeneration of MM and therapeutic resistance.Methods and ResultsTo evaluate the contribution of ADAR1 modulation to global RNA editing changes and differential gene expression, we performed whole transcriptome sequencing of primary MM and PCL samples that were lentivirally transduced with shRNA targeting human ADAR1 compared to vector control shRNA. Analysis at the single nucleotide level revealed that 20-50% knockdown of ADAR1 was sufficient to induce substantial downregulation of A-to-I editing rates throughout the transcriptome, particularly at 3'UTR loci, along with specific modulation of extracellular matrix and inflammasome-associated gene expression patterns. Moreover, in contrast to lentiviral ADAR1 shRNA knockdown and overexpression of an editase defective ADAR1 mutant (ADAR1E912A), lentiviral wild-type ADAR1 overexpression enhanced editing of GLI1, a Hedgehog (Hh) pathway transcriptional activator and self-renewal agonist. Editing of GLI1 transcripts enhanced GLI transcriptional activity in luciferase reporter assays, and promoted lenalidomide resistance in vitro. Finally, lentiviral shRNA ADAR1 knockdown reduced regeneration of high-risk MM in humanized serial transplantation mouse models, indicative of reduced malignant self-renewal capacity. Notably, in human myeloma cells analyzed using NanoString nCounter assays, overexpression of wild-type versus edited GLI1 elicited distinct gene expression changes also in extracellular matrix and immune response genes. These data demonstrate that ADAR1 promotes malignant self-renewal of MM and if selectively inhibited may prevent progression and relapse through modulation of global A-to-I RNA editing and extracellular and immune response gene expression.ConclusionsDeregulated RNA editing, driven by aberrant ADAR1 activation, represents a unique source of transcriptomic and proteomic diversity, resulting in self-renewal of MM cells in inflammatory microenvironments. In summary, both genetic (1q21 amplification) and microenvironmental factors (inflammatory cytokines, immunomodulatory drugs) combine to drive A-to-I RNA editing-dependent malignant regeneration in MM through inflammasome and extracellular matrix gene pathway remodeling. These effects can be down-modulated even with small reductions in ADAR1 expression and activity. Thus, ADAR1 represents both a vital prognostic biomarker and therapeutic target in MM. DisclosuresCostello:Celgene: Consultancy; Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy.

Parity-dependent association between IL-12Râ2 and IL-23R gene polymorphisms and clinical mastitis in Chinese Holstein cows

Interleukin-12 (IL-12) and interleukin-23 (IL-23) are proinflammatory cytokines produced by macrophages and dendritic cells in response to infection with intracellular pathogens. Given the importance of IL-12 and IL-23 for modulating inflammation and the host immune response, the IL-12 and IL-23 receptor genes may be suitable candidate genes for studying disease resistance in dairy cattle. DNA samples of twenty Chinese Holstein cows were selected randomly for PCR amplification and sequencing, and used for SNP discovery in the bovine IL-12Râ2 and IL-23R promoter regions. One SNP (c.-246G&gt;T, rs385343195) in IL-12Râ2 and 2 SNPs [c.-856A&gt;G (rs109216732) and c.-207T&gt;C (rs109571825)] in IL-23R were identified. Identified SNPs were genotyped in 866 Chinese Holstein cows and associations between SNPs or haplotypes and clinical mastitis infection were analyzed by logistic regression model. Significant associations between rs385343195 (IL-12Râ2 gene) and haplotypes of SNPs rs385343195-rs109216732-rs109571825 (TGC and TAT), and clinical mastitis infection were detected depending on parity, and this provides insight into the complex mechanisms of immunity to infections. Further investigations are required to reveal the mechanisms of IL-12Râ2 and IL-23R in mastitis susceptibility in cattle.

Low Interleukin-7 Receptor Messenger RNA Expression Is Independently Associated With Day 28 Mortality in Septic Shock Patients.

Septic shock is the primary cause of death in ICUs. A better comprehension of its pathophysiology, in particular, the immune alteration mechanisms, opened new therapeutic perspectives such as the recombinant interleukin-7. The use of biomarkers could improve the identification of eligible patients for this therapy. The soluble form of the interleukin-7 appears as a promising candidate in this regard since an association between its high plasmatic level and mortality in critically ill patients has been demonstrated. Because there are no data available on the transcriptional regulation of the interleukin-7 receptor in such patients, this study aimed to explore the expression level of different interleukin-7 receptor transcripts after septic shock and evaluate their association with mortality. Retrospective discovery cohort (30 patients) and validation cohort (177 patients). Two French ICUs (discovery study) and six French ICUs (validation study). Adult septic shock patients. None. The quantification of several interleukin-7 receptor transcripts using specific reverse transcription quantitative polymerase chain reaction designs allowed for global evaluation of interleukin-7 receptor gene expression in whole blood. In the discovery cohort, all interleukin-7 receptor transcripts studied were expressed at lower levels in septic shock patients than in healthy volunteers. Interleukin-7 receptor gene expression at day 3 after septic shock diagnosis was associated with day 28 mortality. Patients at a lower risk of death showed higher expression levels. These results were confirmed in the independent validation cohort. Interestingly, using a threshold obtained on the discovery cohort, we observed in the validation cohort a high negative predictive value for day 28 mortality for the transcript encoding the membrane form of interleukin-7 receptor (0.86; 95% CI, 0.79-0.93). Interleukin-7 receptor transcripts appear as biomarkers of impaired adaptive immune response in septic shock patients and as a promising tool for patient stratification in clinical trials evaluating immunoadjuvant therapies.