The Cytoprotective Effects of the Glycoprotein 130 Receptor-coupled Cytokine, Cardiotrophin-1, Require Activation of NF-κB

• Published in: The Journal of biological chemistry 2001-10, Vol.276 (40), p.37621-37629
• Main Authors: Craig, Rian, Wagner, Mylo, McCardle, Trevor, Craig, A. Grey, Glembotski, Christopher C.
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport - drug effects; cardiotrophin 1; Cell Hypoxia; Cells, Cultured; CT-1 protein; Cytokines - pharmacology; Enzyme Activation - drug effects; I-kappa B Proteins - metabolism; Mitogen-Activated Protein Kinases - metabolism; Myocardium - cytology; Myocardium - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases; p38 protein; Phosphatidylinositol 3-Kinases - metabolism; Protective Agents - pharmacology; Rats; Rats, Sprague-Dawley; Signal Transduction; Transcription, Genetic - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M103276200

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-κB cytosolic anchor, IκB, as well as the translocation of the p65 subunit of NF-κB to the nucleus and increased expression of an NF-κB-dependent reporter gene. Inhibitors of the p38, ERK, or Akt pathways each partially reduced CT-1-mediated NF-κB activation, as well as the cytoprotective effects of CT-1 against hypoxic stress. Together, the inhibitors completely blocked CT-1-dependent NF-κB activation and cytoprotection. A cell-permeable peptide that selectively disrupted NF-κB 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-κB and that NF-κB is required for CT-1 to mediate its full cytoprotective effects in cardiac myocytes.