A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis

• Published in: Scientific reports 2017-08, Vol.7 (1), p.10180, Article 10180
• Main Authors: Díaz-Jiménez, David, Núñez, Lucía, De la Fuente, Marjorie, Dubois-Camacho, Karen, Sepúlveda, Hugo, Montecino, Martín, Torres-Riquelme, Alejandro, García-González, Paulina, Chnaiderman, Jonás, Vossenkamper, Anna, MacDonald, Thomas T., Simian, Daniela, González, María-Julieta, Cidlowski, John A., Quera, Rodrigo, Hermoso, Marcela A.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/21; 13/31; 13/44; 14/19; 38/70; 45/15; 45/23; 45/77; 45/90; 631/250/256/2515; 692/4020/1503/257/1389; Adrenal Cortex Hormones - pharmacology; Adrenal Cortex Hormones - therapeutic use; Adult; Anti-inflammatory agents; Cells, Cultured; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - genetics; Colitis, Ulcerative - metabolism; Corticoids; Corticosteroids; Dexamethasone; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Enzyme-linked immunosorbent assay; Female; Gene Expression Regulation - drug effects; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Glucocorticoids; Humanities and Social Sciences; Humans; Inflammatory bowel disease; Inflammatory bowel diseases; Interleukin 1; Interleukin-1 Receptor-Like 1 Protein - genetics; Interleukin-1 Receptor-Like 1 Protein - metabolism; Intestinal Mucosa - cytology; Intestinal Mucosa - metabolism; Intestine; Leukocytes; Male; Middle Aged; Mucosa; multidisciplinary; Polymorphism, Single Nucleotide; Promoter Regions, Genetic - drug effects; Science; Science (multidisciplinary); Sequence Analysis, DNA; Signal transduction; Single-nucleotide polymorphism; Transcription; Ulcerative colitis; Up-Regulation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-10465-0

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.