TNF receptor-activated factor 2 mediates cardiac protection through noncanonical NF-κB signaling
TNF receptor-activated factor 2 mediates cardiac protection through noncanonical NF-κB signaling
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DOI：
10.1172/jci.insight.98278
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发表时间：
2018-02-08
期刊：
影响因子：
8
通讯作者：
Mann, Douglas L.
中科院分区：
文献类型：
--
作者：
Evans, Sarah;Tzeng, Huei-Ping;Mann, Douglas L.
为了阐明TNF受体激活因子2（TRAF 2）在心脏中的细胞保护作用的机制，我们在心脏限制性过表达TRAF 2（Myh 6-TRAF 2（LC））的小鼠中进行了离体和体内的遗传获得和功能丧失研究。将Myh 6-TRAF 2（LC）小鼠与缺乏典型信号传导的小鼠（Myh 6-TRAF 2（LC）/Myh 6-I κ B α Δ N）杂交消除了TRAF 2离体的细胞保护作用。相反，抑制JAK/STAT通路并不能消除TRAF 2的细胞保护作用。WT、Myh 6-TRAF 2（LC）和Myh 6-TRAF 2（LC）/Myh 6-I κ B α Delta N小鼠心脏的转录谱表明，非经典NF-κ B信号传导途径在Myh 6-TRAF 2（LC）小鼠心脏中上调。对来自未处理的12周龄WT、Myh 6-TRAF 2（LC）和Myh 6-TRAF 2（LC）/Myh 6-I κ B α Delta N小鼠心脏的核和细胞质提取物上的NF-κ B家族蛋白质p50、p65、p52和RelB的Western印迹和ELISA显示p52和RelB的表达水平和DNA结合增加，而p50和p65亚基的表达或DNA结合没有增加。将Myh 6-TRAF 2（LC）小鼠与RelB（-/+）小鼠杂交（Myh 6-TRAF 2（LC）/RelB（-/+））减弱了TRAF 2离体和体内的细胞保护作用。综合来看，这些结果表明，经典和非经典NF-κ B信号通路之间的串扰是介导TRAF 2的细胞保护作用所必需的。
To elucidate the mechanisms responsible for cytoprotective effects of TNF receptor-activated factor 2 (TRAF2) in the heart, we employed genetic gain-and loss-of-function studies ex vivo and in vivo in mice with cardiac-restricted overexpression of TRAF2 (Myh6-TRAF2(LC)). Crossing Myh6-TRAF2(LC) mice with mice lacking canonical signaling (Myh6-TRAF2(LC) /Myh6-I kappa B alpha Delta N) abrogated the cytoprotective effects of TRAF2 ex vivo. In contrast, inhibiting the JAK/STAT pathway did not abrogate the cytoprotective effects of TRAF2. Transcriptional profiling of WT, Myh6-TRAF2(LC), and Myh6-TRAF2(LC)/Myh6-I kappa B alpha Delta N mouse hearts suggested that the noncanonical NF-kappa B signaling pathway was upregulated in the Myh6-TRAF2(LC) mouse hearts. Western blotting and ELISA for the NF-kappa B family proteins p50, p65, p52, and RelB on nuclear and cytoplasmic extracts from naive 12-week-old WT, Myh6-TRAF2(LC), and Myh6-TRAF2(LC)/Myh6-I kappa B alpha Delta N mouse hearts showed increased expression levels and increased DNA binding of p52 and RelB, whereas there was no increase in expression or DNA binding of the p50 and p65 subunits. Crossing Myh6-TRAF2(LC) mice with RelB(-/+) mice (Myh6-TRAF2(LC)/RelB(-/+)) attenuated the cytoprotective effects of TRAF2 ex vivo and in vivo. Viewed together, these results suggest that crosstalk between the canonical and noncanonical NF-kappa B signaling pathways is required for mediating the cytoprotective effects of TRAF2.