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

Area of Science:

• Immunology
• Genetics
• Gastroenterology

Background:

• The ST2/IL33 signaling pathway is implicated in ulcerative colitis (UC).
• Soluble ST2 (sST2), an anti-inflammatory receptor, increases with corticosteroid treatment in UC patients, but its regulation is unclear.
• The IL1RL1 gene encodes ST2 receptors.

Purpose of the Study:

• To investigate if genetic variants in the IL1RL1 distal promoter are associated with UC.
• To determine if these variants affect glucocorticoid-mediated ST2 expression.

Main Methods:

• ELISA and PCR sequencing were used to analyze serum ST2 levels and IL1RL1 promoter variants in UC patients on corticosteroids.
• Intestinal mucosa cultures assessed glucocorticoid-mediated ST2 production.
• RT-qPCR, ChIP assay, and luciferase reporter assays investigated molecular regulation.
• Dexamethasone's effect on ST2 transcription was analyzed in leukocytes and correlated with IL1RL1 variants.

Main Results:

• SNPs rs6543115(C) and rs6543116(A) in the IL1RL1 distal promoter were associated with elevated sST2 in UC patients receiving corticosteroids.
• Dexamethasone upregulated sST2 transcription by interacting with a glucocorticoid-response element (GRE) containing the rs6543115(C) variant.
• The rs6543115(C) SNP is located within a GRE, suggesting a role in modulating glucocorticoid-induced sST2 expression.

Conclusions:

• IL1RL1 SNPs, particularly rs6543115(C), may confer susceptibility to UC.
• This SNP is within a functional GRE, potentially influencing glucocorticoid-mediated sST2 expression and treatment response in UC.