The cytoprotective effects of the glycoprotein 130 receptor-coupled cytokine, cardiotrophin-1, require activation of NF-κB

被引:75
作者
Craig, R
Wagner, M
McCardle, T
Craig, AG
Glembotski, CC [1 ]
机构
[1] San Diego State Univ, Inst Heart, San Diego, CA 92182 USA
[2] San Diego State Univ, Dept Biol, San Diego, CA 92182 USA
[3] Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, La Jolla, CA 92037 USA
关键词
D O I
10.1074/jbc.M103276200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Many cell types mount elaborate, compensatory responses to stress that enhance survival; however, the intracellular signals that govern these responses are poorly understood. Cardiotrophin-1 (CT-1), a stress-induced cytokine, belongs to the interleukin-6/glycoprotein 130 receptor-coupled cytokine family. CT-1 is released from the heart in response to hypoxic stress, and it protects cardiac myocytes from hypoxia-induced apoptosis, thus establishing a central role for this cytokine in the cardiac stress response. In the present study, CT-1 activated p38 and ERK MAPKs as well as Akt in cultured cardiac myocytes; these three pathways were activated in a parallel manner. CT-1 also induced the degradation of the NF-kappaB cytosolic anchor, I kappaB, as well as the translocation of the p65 subunit of NF-kappaB to the nucleus and increased expression of an NF-kappaB-dependent reporter gene. Inhibitors of the p38, ERK, or ARt pathways each partially reduced CT-1-mediated NF-kappaB activation, as well as the cytoprotective effects of CT-1 against hypoxic stress. Together, the inhibitors completely blocked CT-1-dependent NF-kappaB activation and cytoprotection. A cell-permeable peptide that selectively disrupted NF-kappaB activation also completely inhibited the cytoprotective effects of CT-1. These results indicate that CT-1 signals through p38, ERK, and Akt in a parallel manner to activate NF-kappaB and that NF-kappaB is required for CT-1 to mediate its full cytoprotective effects in cardiac myocytes.
引用
收藏
页码:37621 / 37629
页数:9
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