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

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.