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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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 2

IL-33 blocks prohypertrophic stimuli in cardiomyocytes and sST2 inhibits IL-33.

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IL-33 blocks prohypertrophic stimuli in cardiomyocytes and sST2 inhibits...
(A) IL-33 demonstrated a nonsignificant trend toward stimulating hypertrophy, but IL-33 blocked angiotensin II– and phenylephrine-induced (Phe) leucine uptake in a dose-dependent manner. (B) sST2 dose-dependently reversed the antihypertrophic effect of IL-33 under angiotensin II and phenylephrine. (C) Anti-ST2L monoclonal antibody, which blocks membrane-bound ST2L receptor–binding activity, blocked the antihypertrophic effect of IL-33, unlike control IgG. (D) Leucine uptake was not affected by sST2 compared with either baseline or control protein IL-1R–related protein 2 (IL-1Rrp2), but further enhanced hypertrophy under angiotensin II and phenylephrine. Data are from 3–5 sets of experiments. (E) Quantitative analysis of in vitro cell size measurements of cardiomyocytes was consistent with leucine incorporation assays (n = 200 each). *P < 0.05 versus baseline; #P < 0.05. (F) Induced secretion of both sST2 and IL-33 can reduce free IL-33. Cardiac fibroblasts were treated with indicated doses of PMA for 24 hours to induce sST2 and IL-33. In the top blots, conditioned media (20 μl) were analyzed by Western analysis. PMA dose-dependently increased secretion of both IL-33 and sST2. Below, media were preincubated in the presence or absence of 20 μg sST2-Fc protein and then incubated with presaturated beads for 2 hours. Samples preincubated with sST2-Fc had little IL-33, indicating that preincubation with sST2-Fc removed free IL-33. PMA dose-dependently decreased free IL-33 despite an increase in overall IL-33; these data suggest that induced sST2 can function as a decoy receptor, decreasing free IL-33.