Interleukin 35 ameliorates myocardial ischemia-reperfusion injury by activating the gp130-STAT3 axis
Interleukin 35 ameliorates myocardial ischemia-reperfusion injury by activating the gp130-STAT3 axis
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白细胞介素35通过激活gp130-STAT3轴改善心肌缺血再灌注损伤
DOI：
10.1096/fj.201901718rr
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发表时间：
2020-01-09
期刊：
影响因子：
4.8
通讯作者：
Cheng, Xiang
中科院分区：
文献类型：
--
作者：
Zhou, Xingdi;Xia, Ni;Cheng, Xiang
心肌缺血再灌注损伤（MIRI）是临床常见的并发症，对急性心肌梗死（AMI）的治疗提出了挑战。白细胞介素35（IL-35）通过与gp 130、IL-12 R β 2和IL-27 R α受体的结合而表现出抗炎特性。然而，IL-35是否在MIRI的治疗中发挥有益作用以及潜在的潜在机制尚不清楚。我们发现，IL-35在小鼠模型中通过减少梗死面积和心肌肌钙蛋白T，改善心脏功能和减少心肌细胞凋亡来保护MIRI。尽管IL-35激活了心脏中的STAT 3和STAT 5磷酸化，但信号转导和转录激活因子3（STAT 3）对于介导IL-35介导的对心肌细胞特异性STAT 3缺陷小鼠MIRI的保护作用至关重要。此外，gp 130是IL-35诱导的STAT 3激活和心脏保护所必需的。有趣的是，IL-35在心肌细胞中诱导gp 130同源二聚体和gp 130/IL-12 R β 2异源二聚体。我们的研究结果表明，IL-35可以通过一个新的信号通路，IL-35-gp 130-STAT 3通路，在心肌细胞中执行对MIRI的保护作用，这可能是有益的，新的和有效的治疗方法的发展，以治疗MIRI。
Myocardial ischemia-reperfusion injury (MIRI) is common clinical complication, which represents significant challenge in the treatment of acute myocardial infarction (AMI) diseases. Interleukin 35 (IL-35) exhibits anti-inflammatory properties via the engagement of the gp130, IL-12R beta 2 and IL-27R alpha receptors. However, whether IL-35 plays a beneficial role in the treatment of MIRI and potential underling mechanism are unclear. We showed that IL-35 conferred protection from MIRI as demonstrated by reduced infarct size and cardiac troponin T, improved cardiac function and decreased cardiomyocyte apoptosis in a mouse model. Despite activation of both STAT3 and STAT5 phosphorylation in the heart by IL-35, signal transducers and activators of transcription 3 (STAT3) was essential for mediating the IL-35-mediated protective effect on MIRI using cardiomyocyte-specific STAT3 deficient mice. Furthermore, gp130 was required for the STAT3 activation and cardio-protection induced by IL-35. Interestingly, IL-35 induced gp130 homodimer and gp130/IL-12R beta 2 heterodimers in cardiomyocyte. Our results indicate that IL-35 can execute a protective role against MIRI through a novel signaling pathway, IL-35-gp130-STAT3 pathway, in cardiomyocytes, which may be beneficial for the development of novel and effective therapeutic approaches to treat the MIRI.