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

David Díaz-Jiménez; Lucía Núñez; Marjorie De La Fuente; Karen Dubois-Camacho; Hugo Sepúlveda; Martín Montecino; Alejandro Torres-Riquelme; Paulina García-González; Jonás Chnaiderman; Anna Vossenkamper; Thomas T. MacDonald; Daniela Simian; María Julieta González; John A. Cidlowski; Rodrigo Quera; Marcela A. Hermoso

doi:10.1038/s41598-017-10465-0

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

David Díaz-Jiménez, Lucía Núñez, Marjorie De La Fuente, Karen Dubois-Camacho, Hugo Sepúlveda, Martín Montecino, Alejandro Torres-Riquelme, Paulina García-González, Jonás Chnaiderman, Anna Vossenkamper, Thomas T. MacDonald, Daniela Simian, María Julieta González, John A. Cidlowski, Rodrigo Quera^*, Marcela A. Hermoso

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

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.

Original language	English
Article number	10180
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-10465-0
State	Published - 1 Dec 2017
Externally published	Yes

Bibliographical note

Funding 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.

Publisher Copyright:
© 2017 The Author(s).

Keywords

Adrenal Cortex Hormones
Adult
Cells, Cultured
Colitis, Ulcerative
Dexamethasone
Female
Gene Expression Regulation
Genetic Predisposition to Disease
Humans
Interleukin-1 Receptor-Like 1 Protein
Intestinal Mucosa
Male
Middle Aged
Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Sequence Analysis, DNA; Up-Regulation
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Sequence Analysis, DNA
Up-Regulation

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Díaz-Jiménez, D., Núñez, L., De La Fuente, M., Dubois-Camacho, K., Sepúlveda, H., Montecino, M., Torres-Riquelme, A., García-González, P., Chnaiderman, J., Vossenkamper, A., MacDonald, T. T., Simian, D., González, M. J., Cidlowski, J. A., Quera, R., & Hermoso, M. A. (2017). A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis. Scientific Reports, 7(1), Article 10180. https://doi.org/10.1038/s41598-017-10465-0

@article{376a9ba3d3b74583824fdd1651776403,

title = "A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis",

abstract = "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.",

keywords = "Adrenal Cortex Hormones, Adult, Cells, Cultured, Colitis, Ulcerative, Dexamethasone, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Interleukin-1 Receptor-Like 1 Protein, Intestinal Mucosa, Male, Middle Aged, Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Sequence Analysis, DNA; Up-Regulation, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Sequence Analysis, DNA, Up-Regulation",

author = "David D{\'i}az-Jim{\'e}nez and Luc{\'i}a N{\'u}{\~n}ez and {De La Fuente}, Marjorie and Karen Dubois-Camacho and Hugo Sep{\'u}lveda and Mart{\'i}n Montecino and Alejandro Torres-Riquelme and Paulina Garc{\'i}a-Gonz{\'a}lez and Jon{\'a}s Chnaiderman and Anna Vossenkamper and MacDonald, {Thomas T.} and Daniela Simian and Gonz{\'a}lez, {Mar{\'i}a Julieta} and Cidlowski, {John A.} and Rodrigo Quera and Hermoso, {Marcela A.}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41598-017-10465-0",

language = "English",

volume = "7",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Díaz-Jiménez, D, Núñez, L, De La Fuente, M, Dubois-Camacho, K, Sepúlveda, H, Montecino, M, Torres-Riquelme, A, García-González, P, Chnaiderman, J, Vossenkamper, A, MacDonald, TT, Simian, D, González, MJ, Cidlowski, JA, Quera, R & Hermoso, MA 2017, 'A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis', Scientific Reports, vol. 7, no. 1, 10180. https://doi.org/10.1038/s41598-017-10465-0

TY - JOUR

T1 - A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis

AU - Díaz-Jiménez, David

AU - Núñez, Lucía

AU - De La Fuente, Marjorie

AU - Dubois-Camacho, Karen

AU - Sepúlveda, Hugo

AU - Montecino, Martín

AU - Torres-Riquelme, Alejandro

AU - García-González, Paulina

AU - Chnaiderman, Jonás

AU - Vossenkamper, Anna

AU - MacDonald, Thomas T.

AU - Simian, Daniela

AU - González, María Julieta

AU - Cidlowski, John A.

AU - Quera, Rodrigo

AU - Hermoso, Marcela A.

N1 - Funding 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. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Adrenal Cortex Hormones

KW - Adult

KW - Cells, Cultured

KW - Colitis, Ulcerative

KW - Dexamethasone

KW - Female

KW - Gene Expression Regulation

KW - Genetic Predisposition to Disease

KW - Humans

KW - Interleukin-1 Receptor-Like 1 Protein

KW - Intestinal Mucosa

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Sequence Analysis, DNA; Up-Regulation

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Sequence Analysis, DNA

KW - Up-Regulation

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U2 - 10.1038/s41598-017-10465-0

DO - 10.1038/s41598-017-10465-0

M3 - Article

C2 - 28860510

AN - SCOPUS:85028706254

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 10180

ER -

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

Abstract

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Keywords

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