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-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.

• Authors: Shoji Sanada, Daihiko Hakuno, Luke J Higgins, Eric R Schreiter, Andrew N J McKenzie, Richard T Lee
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 6 Pg. 1538-49 (Jun 2007) ISSN: 0021-9738 [Print] United States
• PMID: 17492053 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• IL1RL1 protein, human
• IL33 protein, human
• Il1rl1 protein, mouse
• Il33 protein, mouse
• Interleukin-1 Receptor-Like 1 Protein
• Interleukin-33
• Interleukins
• Membrane Proteins
• NF-kappa B
• Receptors, Cell Surface
• Receptors, Interleukin
• Recombinant Proteins

Topics

• Animals
• Biomechanical Phenomena
• Cardiotonic Agents (metabolism, pharmacology)
• Cells, Cultured
• Fibroblasts (metabolism)
• Humans
• Interleukin-1 Receptor-Like 1 Protein
• Interleukin-33
• Interleukins (metabolism, pharmacology)
• Membrane Proteins (deficiency, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• NF-kappa B (metabolism)
• Rats
• Receptors, Cell Surface (metabolism)
• Receptors, Interleukin
• Recombinant Proteins (pharmacology)
• Signal Transduction