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

Rian Craig, Mylo Wagner, Trevor McCardle, A. Grey Craig, Christopher C. Glembotski

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)37621-37629
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number40
DOIs
StatePublished - Oct 5 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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