Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA.
J Mol Cell Cardiol. 2010 Oct;49(4):655-63. doi: 10.1016/j.yjmcc.2010.05.007. Epub 2010 Jun 9.
The transmembrane glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN), and the pleiotropic proinflammatory cytokine interleukin (IL)-18, play critical roles in myocardial remodeling, by inducing matrix degrading metalloproteinases (MMPs). Previously we showed that IL-18 induces EMMPRIN expression in cardiomyocytes via MyD88/IRAK4/TRAF6/JNK-dependent Sp1 activation. Here in reciprocal studies we demonstrate that EMMPRIN is a potent inducer of IL-18 transcription, protein expression and protein secretion in primary mouse cardiomyocytes. We show for the first time that EMMPRIN stimulates the activation of NF-kappaB, AP-1, CREB, and ATF-2 in cardiomyocytes, and induces IL-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB and MKK7/JNK/AP-1 signaling. Moreover, EMMPRIN induces robust time-dependent induction of various MMP mRNAs. EMMPRIN also induces the mRNA of TIMPs 1 and 3, but in a delayed fashion. These results suggest that IL-18-induced EMMPRIN expression may favor net MMP expression and ECM destruction, and thus identify both as potential therapeutic targets in countering adverse myocardial remodeling.
细胞外基质金属蛋白酶诱导因子（EMMPRIN）是一种跨膜糖蛋白，白细胞介素（IL）-18 是一种多功能促炎细胞因子，它们在心肌重构中起着关键作用，可诱导细胞外基质降解金属蛋白酶（MMPs）。我们之前的研究表明，IL-18 通过 MyD88/IRAK4/TRAF6/JNK 依赖性 Sp1 激活诱导心肌细胞中 EMMPRIN 的表达。在相互的研究中，我们证明 EMMPRIN 是原代小鼠心肌细胞中 IL-18 转录、蛋白表达和蛋白分泌的有效诱导剂。我们首次表明，EMMPRIN 刺激心肌细胞中 NF-κB、AP-1、CREB 和 ATF-2 的激活，并通过 Rac1 依赖性 PI3K/Akt/IKK/NF-κB 和 MKK7/JNK/AP-1 信号通路诱导 IL-18 表达。此外，EMMPRIN 还可诱导各种 MMP mRNAs 的时间依赖性诱导。EMMPRIN 还诱导 TIMP1 和 TIMP3 的 mRNA 表达，但呈延迟方式。这些结果表明，IL-18 诱导的 EMMPRIN 表达可能有利于 MMP 表达和细胞外基质的破坏，因此可将两者均作为对抗心肌重构不良的潜在治疗靶点。
