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

Many cell types mount elaborate, compensatory responses to stress that enha nce survival; however, the intracellular signals that govern these response s are poorly understood. Cardiotrophin-1 (CT-1), a stress-induced cytokine, belongs to the interleukin-6/glycoprotein 130 receptor-coupled cytokine fa mily. CT-1 is released from the heart in response to hypoxic stress, and it protects cardiac myocytes from hypoxia-induced apoptosis, thus establishin g a central role for this cytokine in the cardiac stress response. In the p resent study, CT-1 activated p38 and ERK MAPKs as well as Akt in cultured c ardiac myocytes; these three pathways were activated in a parallel manner. CT-1 also induced the degradation of the NF-kappaB cytosolic anchor, I kapp aB, as well as the translocation of the p65 subunit of NF-kappaB to the nuc leus and increased expression of an NF-kappaB-dependent reporter gene. Inhi bitors of the p38, ERK, or ARt pathways each partially reduced CT-1-mediate d NF-kappaB activation, as well as the cytoprotective effects of CT-1 again st hypoxic stress. Together, the inhibitors completely blocked CT-1-depende nt NF-kappaB activation and cytoprotection. A cell-permeable peptide that s electively disrupted NF-kappaB activation also completely inhibited the cyt oprotective effects of CT-1. These results indicate that CT-1 signals throu gh 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.