Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling
Jennifer E. Ho, Wei-Yu Chen, Ming-Huei Chen, Martin G. Larson, Elizabeth L. McCabe, Susan Cheng, Anahita Ghorbani, Erin Coglianese, Valur Emilsson, Andrew D. Johnson, Stefan Walter, Nora Franceschini, Christopher J. O’Donnell, CARDIoGRAM Consortium, CHARGE Inflammation Working Group, Abbas Dehghan, Chen Lu, Daniel Levy, Christopher Newton-Cheh, CHARGE Heart Failure Working Group, Honghuang Lin, Janine F. Felix, Eric R. Schreiter, Ramachandran S. Vasan, James L. Januzzi, Richard T. Lee, Thomas J. Wang
Jennifer E. Ho, Wei-Yu Chen, Ming-Huei Chen, Martin G. Larson, Elizabeth L. McCabe, Susan Cheng, Anahita Ghorbani, Erin Coglianese, Valur Emilsson, Andrew D. Johnson, Stefan Walter, Nora Franceschini, Christopher J. O’Donnell, CARDIoGRAM Consortium, CHARGE Inflammation Working Group, Abbas Dehghan, Chen Lu, Daniel Levy, Christopher Newton-Cheh, CHARGE Heart Failure Working Group, Honghuang Lin, Janine F. Felix, Eric R. Schreiter, Ramachandran S. Vasan, James L. Januzzi, Richard T. Lee, Thomas J. Wang
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Research Article Immunology

Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling

Abstract

The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.

Authors

Jennifer E. Ho, Wei-Yu Chen, Ming-Huei Chen, Martin G. Larson, Elizabeth L. McCabe, Susan Cheng, Anahita Ghorbani, Erin Coglianese, Valur Emilsson, Andrew D. Johnson, Stefan Walter, Nora Franceschini, Christopher J. O’Donnell, Abbas Dehghan, Chen Lu, Daniel Levy, Christopher Newton-Cheh, Honghuang Lin, Janine F. Felix, Eric R. Schreiter, Ramachandran S. Vasan, James L. Januzzi, Richard T. Lee, Thomas J. Wang

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Figure 5

IL-33–induced sST2 expression is enhanced with mTOR inhibition and occurs via ST2L-dependent signaling.

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IL-33–induced sST2 expression is enhanced with mTOR inhibition and occur...
(A) sST2 mRNA expression in KU812 cells after treatment with DMSO, IL-33, or IL-33 plus signal inhibitors (wortmannin, LY294002, rapamycin, PD98059, SP60125, BAY11-7082, or SR11302). (B) ST2L mRNA and (C) sST2 mRNA expression in KU812 cells treated with PBS (white columns), rapamycin (rapa), anti-ST2 mAb, IL-33, IL-33 plus anti-ST2, IL-33 plus rapamycin, IL-33 plus rapamycin plus anti-ST2 mAb, or rapamycin plus anti-ST2. (D) IL33 mRNA expression in KU812 cells after treatment with DMSO, signal inhibitors, IL-33 plus signal inhibitors, and IL-1β plus signal inhibitors. *P < 0.05 vs. PBS-treated group; #P < 0.05 vs. IL-33–treated group; &P < 0.05 vs. IL-1b–treated group. Error bars represent mean ± SEM from 2 independent experiments. (E) A schematic model illustrating the regulation of sST2 expression by IL1RL1 missense variants through enhanced induction of IL-33 via enhanced NF-κB and AP-1 signaling and enhanced IL-33 responsiveness via increasing ST2L expression.