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 5

IL-33/ST2 signaling is cardioprotective in vivo.

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IL-33/ST2 signaling is cardioprotective in vivo. (A) Echocardiographic a...
(A) Echocardiographic analysis at 4 weeks after operation demonstrated increased left ventricular mass, left ventricular wall thickness, and reduced fractional shortening in ST2–/– mice. Treatment with IL-33 reduced hypertrophy only in WT mice. IL-33 caused no significant change under non-stress conditions in vivo. n = 10 (nonoperated control); 8 (WT sham); 10 (WT TAC); 8 (WT sham + IL-33); 10 (WT TAC + IL-33); 8 (ST2–/– sham); 12 (ST2–/– TAC); 8 (ST2–/– sham + IL-33); and 10 (ST2–/– TAC + IL-33). (B) Representative images and (C) quantitative analysis of mRNA expression of ANP and BNP relative to internal control (18S) in the left ventricle at 1 week after operation, as assessed by Northern analysis. White and black bars indicate sham-operated and TAC, respectively. (D) NF-κB activation from EMSA in vivo 1 week after operation. ANP and BNP expression and NF-κB activity increased in ST2–/– mice compared with WT mice; IL-33 reversed these changes only in WT mice. Positive and negative control mixtures as well as specific competition mixtures and supershift induce by p65 antibody are also shown. *P < 0.05 versus nonoperated control (A) or sham-operated WT (C); ΧP < 0.05 versus the same treatment in WT; †P < 0.05 versus sham in the same group; #P < 0.05.