Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-kappaB/PTEN suppression.
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.
Chandrasekar
Bysani
B
Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, Texas 78229, USA. chandraseka@uthscsa.edu
Boylston
William H
WH
Venkatachalam
Kaliyamurthi
K
Webster
Nicholas J G
NJ
Prabhu
Sumanth D
SD
Valente
Anthony J
AJ
D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; D002352:Carrier Proteins; D053148:Caspase 3; D020536:Enzyme Activators; D051550:I-kappa B Kinase; D020382:Interleukin-18; D009097:Multienzyme Complexes; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051028:bcl-2-Associated X Protein; C499918:ADIPOQ protein, human; C464801:APPL1 protein, human; C494826:BAX protein, human; C494929:PTEN protein, human; C505407:CASP3 protein, human