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

• Published in: The Journal of clinical investigation 2007-06, Vol.117 (6), p.1538-1549
• Main Authors: Sanada, Shoji, Hakuno, Daihiko, Higgins, Luke J, Schreiter, Eric R, McKenzie, Andrew N J, Lee, Richard T
• Format: Article
• Language: English
• Subjects: Animals; Biomechanical Phenomena; Biomechanics; Biomedical research; Cardiomyocytes; Cardiotonic Agents - metabolism; Cardiotonic Agents - pharmacology; Cells, Cultured; Diseases; Fibroblasts; Fibroblasts - metabolism; Gene expression; Heart attacks; Heart cells; Heart diseases; Heart failure; Humans; Hypertrophy; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins - metabolism; Interleukins - pharmacology; Ligands; Medical prognosis; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; NF-kappa B - metabolism; Peptides; Physiology, Pathological; Proteins; Rats; Receptors, Cell Surface - metabolism; Receptors, Interleukin; Recombinant Proteins - pharmacology; Signal Transduction
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci30634

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-kappaB, it inhibited angiotensin II- and phenylephrine-induced phosphorylation of inhibitor of NF-kappa B alpha (I kappa B alpha) and NF-kappaB 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.