Interleukin-17A mediates cardiomyocyte apoptosis through Stat3-iNOS pathway
Interleukin-17A mediates cardiomyocyte apoptosis through Stat3-iNOS pathway
复制标题
Interleukin-17A通过Stat3-iNOS途径介导心肌细胞凋亡
DOI：
10.1016/j.bbamcr.2016.08.013
复制
发表时间：
2016-11-01
影响因子：
5.1
通讯作者：
Xiang, Meixiang
中科院分区：
文献类型：
--
作者：
Su, Sheng-an;Yang, Du;Xiang, Meixiang
白细胞介素-17A是一种促炎细胞因子，对心肌细胞具有直接的促凋亡作用。但具体机制尚未明确。本研究采用IL-17 A诱导的体外心肌细胞凋亡模型，探讨iNOS和Stat 3在其中的作用。我们的数据表明，新生小鼠心肌细胞表达IL-17受体：IL-17 RA和IL-17 RC，但不表达IL-17 A。外源性IL-17 A可显著诱导心肌细胞iNOS表达，并诱导心肌细胞凋亡。此外，IL-17 A诱导的心肌细胞凋亡可以通过iNOS激活直接实现。我们进一步表明，外源性IL-17 A同时触发Stat 3激活，这反过来又抑制了IL-17 A诱导的心肌细胞iNOS表达。ChIP和双荧光素酶结果均证实Stat 3通过与其特异性启动子区结合直接抑制iNOS的转录活性。与这些数据一致，Stat 3的沉默实际上可以加重IL-17 A触发的心肌细胞凋亡。最后，使用在体心肌缺血/再灌注损伤模型，我们验证了Stat 3抑制增加iNOS表达和加剧心肌细胞凋亡。因此，我们的数据强烈支持这样的观点，即Stat 3通过抑制iNOS转录在IL-17 A/iNOS介导的心肌细胞凋亡中发挥代偿性抗凋亡作用，提供了凋亡调节的新分子机制以及IL-17 A/iNOS和IL-17 A/Stat 3信号传导之间的复杂相互作用。(C)© 2016 Elsevier B. V.版权所有。
Interleukin-17A, a pro-inflammatory cytokine, has a direct proapoptotic effect on cardiomyocytes. However, the specific mechanism has not been clarified. In the present study, an in-vitro model of cardiomyocyte apoptosis induced by IL-17A stimulation was employed and the roles of iNOS and Stat3 involved were investigated. Our data showed that the neonatal mouse cardiomyocytes express IL-17 receptors: IL-17RA and IL-17RC, but did not express IL-17A. Exogenous IL-17A significantly induces iNOS expression and hence the cardiomyocyte apoptosis. Moreover, IL-17A-induced cardiomyocyte apoptosis can be achieved directly via iNOS activation. We further showed that exogenous IL-17A simultaneously triggers Stat3 activation, which in turn inhibits IL-17A-induced iNOS expression in cardiomyocytes. And both ChIP and dual-luciferase results confirmed that Stat3 directly inhibits transcriptional activities of iNOS via binding to its specific promoter region. Consistent with these data, silencing of Stat3 in fact can aggravate IL-17A-triggered cardiomyocyte apoptosis. Finally, using an in vivo myocardial ischemia/reperfusion injury model, we verified that Stat3 inhibition increased iNOS expression and exacerbated cardiomyocyte apoptosis. Thus, our data strongly support the notion that Stat3 plays a compensatory anti-apoptotic role in IL-17A/iNOS-mediated cardiomyocyte apoptosis via inhibiting iNOS transcription, providing a novel molecular mechanism of apoptosis regulation and complicated interactions between IL-17A/iNOS and IL-17A/Stat3 signalings. (C) 2016 Elsevier B.V. All rights reserved.