IL-33 and ST2 comprise a critical biomechanically induced and card ioprotective signaling system
IL-33 and ST2 comprise a critical biomechanically induced and card ioprotective signaling system
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DOI：
10.1172/jci30634
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发表时间：
2007-06-01
影响因子：
15.9
通讯作者：
Lee, Richard T.
中科院分区：
文献类型：
--
作者：
Sanada, Shoji;Hakuno, Daihiko;Lee, Richard T.
ST2是IL-1受体家族的成员，有跨膜型(ST2L)和可溶性(Sst2)两种亚型。Sst2是一种机械诱导的心肌细胞蛋白，血清Sst2水平可预测急性心肌梗死或慢性心力衰竭患者的预后。最近，IL-33被确定为ST2L的一个功能配体，从而可以探索ST2在心肌中的作用。我们发现IL-33是一种生物力学诱导蛋白，主要由心脏成纤维细胞合成。IL-33明显拮抗血管紧张素II和苯肾上腺素诱导的心肌细胞肥大。尽管IL-33激活了核因子-kappa B，但它抑制了血管紧张素II和苯肾上腺素诱导的核转录因子-kappa Bα抑制物(I-kappa Bα)的磷酸化和核因子-kappaB核结合活性。Sst2可阻断IL-33的抗营养作用，提示Sst2在心肌中作为一种可溶性诱饵受体发挥作用。与WT仔鼠相比，ST2(-/-)小鼠出现了更多的左心室肥厚、更多的内腔扩张、更少的短轴缩短率、更多的纤维化和生存障碍。此外，重组IL-33治疗减少了WT小鼠TAC后的肥大和纤维化，并提高了存活率，但对ST2/-窝鼠没有影响。因此，IL-33/ST2信号是一种机械激活的、心脏保护的成纤维细胞-心肌细胞旁分泌系统，我们认为这是一个新的系统。IL-33可能有治疗潜力，有益于调节心肌对超负荷的反应。
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-kappa B, it inhibited angiotensin II- and phenylephrine-induced phosphorylation of inhibitor of NF-kappa B alpha (I kappa B alpha) and NF-kappa B nuclear binding activity. sST2 blocked antiltypertrophic 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.