Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-kappaB/PTEN suppression.

Academic Article

Abstract

  • The adipocyte-derived cytokine adiponectin is known to exert anti-inflammatory and anti-apoptotic effects. In patients with atherosclerotic cardiovascular disease, circulating levels of adiponectin correlate inversely with those of the proinflammatory, proapoptotic cytokine interleukin (IL)-18. The opposing actions of IL-18 and adiponectin on both cell survival and inflammation led us to investigate whether adiponectin signaling antagonizes IL-18-mediated endothelial cell death and to identify the underlying molecular mechanisms. Treatment with IL-18 suppressed Akt phosphorylation and its associated kinase activity, induced IkappaB kinase (IKK)-NF-kappaB-dependent PTEN activation, and promoted endothelial cell death. Pretreatment with adiponectin stimulated APPL1-dependent AMPK activation, reversed Akt inhibition in a phosphatidylinositol 3-kinase-dependent manner, blocked IKK-NF-kappaB-PTEN signaling, reduced caspase-3 activity, blocked Bax translocation, and inhibited endothelial cell death. The cytoprotective effect of adiponectin signaling was recapitulated by treatment with the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-riboside. Collectively, these results demonstrated that adiponectin reverses IL-18-mediated endothelial cell death through an AMPK-associated mechanism, which may thus have therapeutic potential for diminishing IL-18-dependent vascular injury and inflammation.
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    Published In

    Keywords

  • AMP-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Adipocytes, Adiponectin, Carrier Proteins, Caspase 3, Cell Death, Cell Line, Cell Survival, Endothelial Cells, Enzyme Activation, Enzyme Activators, Humans, I-kappa B Kinase, Inflammation, Interleukin-18, Multienzyme Complexes, NF-kappa B, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Protein-Serine-Threonine Kinases, Signal Transduction, bcl-2-Associated X Protein
  • Digital Object Identifier (doi)

    Author List

  • Chandrasekar B; Boylston WH; Venkatachalam K; Webster NJG; Prabhu SD; Valente AJ
  • Start Page

  • 24889
  • End Page

  • 24898
  • Volume

  • 283
  • Issue

  • 36