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.
Bibliographical noteFunding Information:
Funding Grant support was provided by FONDECYT 1110381 (RQ), Uapoya N° 560959, FONDECYT 1120577 and 1170648 (MAH), DA-CLC 2009 (RQ, MAH), DA-CLC 2011-014 (RQ, MAH, DDJ), the CONICYT DOCTORADO NACIONAL 21150264 fellowship and Supplemental Pre-doc Fellowship in the NIH Research Program (Award 37432) (DDJ), and the MECESUP fellowship (KDC). We thank B. Knowles (Siriraj Center of Excellence for Stem Cell Research, Mahidol University, Thailand), R. Oakley and C. Jewell (National Institutes of Environmental Health Sciences, NIH, USA) for their comments and suggestions. Figures were produced using Servier Medical Art on http://www.servier.com.
© 2017 The Author(s).
- Adrenal Cortex Hormones
- Cells, Cultured
- Colitis, Ulcerative
- Gene Expression Regulation
- Genetic Predisposition to Disease
- Interleukin-1 Receptor-Like 1 Protein
- Intestinal Mucosa
- Middle Aged
- Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Sequence Analysis, DNA; Up-Regulation
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Sequence Analysis, DNA