IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system
Shoji Sanada, … , Andrew N.J. McKenzie, Richard T. Lee
Shoji Sanada, … , Andrew N.J. McKenzie, Richard T. Lee
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1538-1549. https://doi.org/10.1172/JCI30634.
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Research Article Cardiology

IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system

Abstract

ST2 is an IL-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. sST2 is a mechanically induced cardiomyocyte protein, and serum sST2 levels predict outcome in patients with acute myocardial infarction or chronic heart failure. Recently, IL-33 was identified as a functional ligand of ST2L, allowing exploration of the role of ST2 in myocardium. We found that IL-33 was a biomechanically induced protein predominantly synthesized by cardiac fibroblasts. IL-33 markedly antagonized angiotensin II– and phenylephrine-induced cardiomyocyte hypertrophy. Although IL-33 activated NF-κB, it inhibited angiotensin II– and phenylephrine-induced phosphorylation of inhibitor of NF-κBα (IκBα) and NF-κB nuclear binding activity. sST2 blocked antihypertrophic effects of IL-33, indicating that sST2 functions in myocardium as a soluble decoy receptor. Following pressure overload by transverse aortic constriction (TAC), ST2–/– mice had more left ventricular hypertrophy, more chamber dilation, reduced fractional shortening, more fibrosis, and impaired survival compared with WT littermates. Furthermore, recombinant IL-33 treatment reduced hypertrophy and fibrosis and improved survival after TAC in WT mice, but not in ST2–/– littermates. Thus, IL-33/ST2 signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which we believe to be novel. IL-33 may have therapeutic potential for beneficially regulating the myocardial response to overload.

Authors

Shoji Sanada, Daihiko Hakuno, Luke J. Higgins, Eric R. Schreiter, Andrew N.J. McKenzie, Richard T. Lee

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Figure 1

IL-33 is induced by mechanical strain in cardiac fibroblasts.

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IL-33 is induced by mechanical strain in cardiac fibroblasts. (A and B) ...
(A and B) Quantitative analyses of gene expression of IL-33 by quantitative PCR (A) and sST2 by Northern analysis (B) in rat neonatal cardiomyocytes (white bars) and fibroblasts (black bars) are shown above with representative images from Northern analyses of cardiac fibroblast RNA. Cells were subjected to cyclic strain (8%, 1 Hz) for the indicated periods. Values are relative to β-tubulin expression and are expressed as percentage of control in cardiac fibroblasts. Data are from at least 3 sets of independent experiments. *P < 0.05, **P < 0.01 versus baseline. (C) Coomassie stain showed that the recombinant mature rat and human IL-33 with N-terminal His tag (10 and 3 μg protein, respectively, was loaded) were of high purity. (D) Pull-down assay of recombinant rat IL-33 with mouse ST2L-Fc protein. The recombinant protein exhibited specific binding to mouse ST2. (E) Western analysis of cardiomyocytes and cardiac fibroblasts subjected to cyclic strain (each 10 μg protein sample from whole cell lysate) for the indicated periods. For reference, 0.1 ng of recombinant IL-33 was applied in the right lane. (F) Representative immunofluorescence microscopy images of left ventricular samples 1 week after sham operation or TAC. Anti-vimentin (top panels) or anti–discoidin domain receptor–2 (DDR-2; bottom panels) antibody was used to detect fibroblasts (red) for dual staining with IL-33 (green). Pressure overload by TAC induced IL-33 expression, particularly in noncardiomyocyte interstitial cells. Scale bar: 10 μm.