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 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-kappa B cytosolic anchor, I kappa B, as well as the translocation of the p65 subunit of NF-kappa B to the nucleus and increased expression of an NF-kappa B-dependent reporter gene. Inhibitors of the p38, ERK, or Akt pathways each partially reduced CT-1-mediated NF-kappa B activation, as well as the cytoprotective effects of CT-1 against hypoxic stress. Together, the inhibitors completely blocked CT-1-dependent NF-kappa B activation and cytoprotection. A cell-permeable peptide that selectively disrupted NF-kappa B 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-kappa B and that NF-kappa B is required for CT-1 to mediate its full cytoprotective effects in cardiac myocytes.
Craig
R
R
San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, California 92182, USA.
Wagner
M
M
McCardle
T
T
Craig
A G
AG
Glembotski
C C
CC
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D020011:Protective Agents; C092073:cardiotrophin 1; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases