A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis.,Scientific Reports

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A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis.
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Aug-31 , DOI: 10.1038/s41598-017-10465-0
David Díaz-Jiménez _{1,

2} , Lucía Núñez ₁ , Marjorie De la Fuente _{1,

3} , Karen Dubois-Camacho ₁ , Hugo Sepúlveda ₄ , Martín Montecino ₄ , Alejandro Torres-Riquelme ₁ , Paulina García-González ₁ , Jonás Chnaiderman ₅ , Anna Vossenkamper ₆ , Thomas T MacDonald ₆ , Daniela Simian ₃ , María-Julieta González ₇ , John A Cidlowski ₂ , Rodrigo Quera ₈ , Marcela A Hermoso ₁

Affiliation

Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, CL, 8380453, Chile.
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
Subdirección de Investigación, Dirección Académica, Clínica Las Condes, Santiago, CL, 7591018, Chile.
Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, and FONDAP Centre for Genome Regulation, Universidad Andres Bello, Santiago, Chile.
Disciplinary Program of Virology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, CL, 8380453, Chile.
Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Cell and Molecular Biology Program, Biomedical Sciences Institute, Faculty of Medicine, Universidad de Chile, Santiago, CL, 8380453, Chile.
Gastroenterology Unit, Clínica Las Condes, Santiago, CL, 7591018, Chile.

The ST2/IL33 signalling pathway has been associated with ulcerative colitis (UC). ST2, encoded by the IL1RL1 gene, is expressed as both a membrane-anchored receptor (ST2L) activated by IL33 and as a soluble receptor (sST2) with anti-inflammatory properties. In UC patients, sST2 is further increased by corticosteroid treatment; however, the glucocorticoid-mediated molecular regulation remains unknown. We therefore tested whether genetic variants in the IL1RL1 distal promoter are involved in UC and affect glucocorticoid-mediated ST2 expression. Serum ST2 levels and genetic variants in the IL1RL1 distal promoter were examined by ELISA and PCR sequencing in UC patients receiving corticosteroids. Glucocorticoid-mediated ST2 production was evaluated in intestinal mucosa cultures. Molecular regulation of glucocorticoid-mediated ST2 was assessed by RT-qPCR, ChIP assay and luciferase reporter assay. Dexamethasone effect on ST2 transcript expression was analyzed in leukocytes and related to IL1RL1 variants. Sequencing of a distal IL1RL1 promoter region demonstrated that SNPs rs6543115(C) and rs6543116(A) are associated with increased sST2 in UC patients on corticosteroids. Dexamethasone up-regulated sST2 transcription through interaction with the glucocorticoid-response element (GRE) carrying rs6543115(C) variant. Our data indicate that IL1RL1 SNPs rs6543115(C) confer susceptibility to UC and is contained in the GRE, which may modulate glucocorticoid-induced sST2 expression.

中文翻译：

功能性 IL1RL1 变体调节溃疡性结肠炎中皮质类固醇诱导的 sST2 表达。

ST2/IL33 信号通路与溃疡性结肠炎 (UC) 相关。ST2 由 IL1RL1 基因编码，表达为由 IL33 激活的膜锚定受体 (ST2L) 和具有抗炎特性的可溶性受体 (sST2)。在 UC 患者中，皮质类固醇治疗会进一步增加 sST2；然而，糖皮质激素介导的分子调控仍然未知。因此，我们测试了 IL1RL1 远端启动子中的遗传变异是否参与 UC 并影响糖皮质激素介导的 ST2 表达。在接受皮质类固醇的 UC 患者中，通过 ELISA 和 PCR 测序检查了 IL1RL1 远端启动子中的血清 ST2 水平和遗传变异。在肠粘膜培养物中评估糖皮质激素介导的 ST2 产生。通过 RT-qPCR、ChIP 测定和荧光素酶报告基因测定评估糖皮质激素介导的 ST2 的分子调节。在白细胞中分析了地塞米松对 ST2 转录物表达的影响，并与 IL1RL1 变体相关。远端 IL1RL1 启动子区域的测序表明，SNP rs6543115(C) 和 rs6543116(A) 与使用皮质类固醇的 UC 患者的 sST2 增加有关。地塞米松通过与携带 rs6543115(C) 变体的糖皮质激素反应元件 (GRE) 相互作用上调 sST2 转录。我们的数据表明 IL1RL1 SNPs rs6543115(C) 赋予 UC 易感性并包含在 GRE 中，这可能调节糖皮质激素诱导的 sST2 表达。远端 IL1RL1 启动子区域的测序表明，SNP rs6543115(C) 和 rs6543116(A) 与使用皮质类固醇的 UC 患者的 sST2 增加有关。地塞米松通过与携带 rs6543115(C) 变体的糖皮质激素反应元件 (GRE) 相互作用上调 sST2 转录。我们的数据表明 IL1RL1 SNPs rs6543115(C) 赋予 UC 易感性并包含在 GRE 中，这可能调节糖皮质激素诱导的 sST2 表达。远端 IL1RL1 启动子区域的测序表明，SNP rs6543115(C) 和 rs6543116(A) 与使用皮质类固醇的 UC 患者的 sST2 增加有关。地塞米松通过与携带 rs6543115(C) 变体的糖皮质激素反应元件 (GRE) 相互作用上调 sST2 转录。我们的数据表明 IL1RL1 SNPs rs6543115(C) 赋予 UC 易感性并包含在 GRE 中，这可能调节糖皮质激素诱导的 sST2 表达。

更新日期：2017-08-31

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