A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis
Author
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Díaz Jiménez, David
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Núñez, Lucía
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Fuente, Marjorie de la
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Dubois Camacho, Karen
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Sepulveda, Hugo
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Montecino, Martin
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Torres Riquelme, Alejandro
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García González, Paulina
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Chnaiderman Figueroa, Jonás
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Vossenkamper, Anna
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MacDonald, Thomas T.
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Simian, Daniela
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González Burgos, María Julieta
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Cidlowski, John A.
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Quera Pino, Rodrigo
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Hermoso Ramello, Marcela
Admission date
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2018-07-09T14:34:02Z
Available date
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2018-07-09T14:34:02Z
Publication date
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2017
Cita de ítem
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Scientific Reports 2017, 7: 10180
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Identifier
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10.1038/s41598-017-10465-0
Identifier
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https://repositorio.uchile.cl/handle/2250/149637
Abstract
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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.
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Patrocinador
dc.description.sponsorship
FONDECYT
1110381
1120577
1170648
Uapoya
560959
CONICYT DOCTORADO NACIONAL
21150264
Supplemental Pre-doc Fellowship in the NIH Research Program
37432
MECESUP fellowship
DA-CLC
2011-014