title: Adiponectin inhibits tumor necrosis factor-α-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation.
abstract: BACKGROUND
  Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered.
  
  
  OBJECTIVE
  The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin's vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling.
  
  
  RESULTS
  Adiponectin significantly reduced tumor necrosis factor (TNF)α-induced intercellular adhesion molecule-1 expression and attenuated TNFα-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P<0.01). AdipoR1-KD markedly reduced globular adiponectin-induced nCDase activation, whereas AdipoR2-KD only slightly reduced. More importantly, small interfering RNA-mediated nCDase-KD markedly blocked the effect of adiponectin on TNFα-induced intercellular adhesion molecule-1 expression. AMP-activated protein kinase-KD failed to block adiponectin-induced nCDase activation and modestly inhibited adiponectin anti-inflammatory effect. In contrast, in caveolin-1 KD (Cav1-KD) cells, >87% of adiponectin-induced nCDase activation was lost. Whereas adiponectin treatment failed to inhibit TNFα-induced intercellular adhesion molecule-1 expression, treatment with sphingosine-1-phosphate or SEW (sphingosine-1-phosphate receptor agonist) remained effective in Cav1-KD cells. AdipoR1 and Cav1 colocalized and coprecipitated in human umbilical vein endothelial cells. Adiponectin treatment did not affect this interaction. There is weak basal Cav1/nCDase interaction, which significantly increased after adiponectin treatment. Knockout of AdipoR1 or Cav1 abolished the inhibitory effect of adiponectin on leukocyte rolling and adhesion in vivo.
  
  
  CONCLUSIONS
  These results demonstrate for the first time that adiponectin inhibits TNFα-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion.
authors.affiliation: From the Department of Emergency Medicine (Y.W., X.W., W.B.L., Y.Y., J.-J.L., X.-L.M.) and Department of Pathology (D.B.), Thomas Jefferson University, Philadelphia, PA; and Department of Physiology, Cardiovascular Research Center (R.S., K.P.) and Center for Translational Medicine (E.G., W.K.), Temple University, Philadelphia, PA.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.forename: David
authors.initials: D
authors.lastname: Booth
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
authors.forename: Kyle
authors.initials: K
authors.lastname: Preston
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Walter
authors.initials: W
authors.lastname: Koch
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
mesh_terms: D052242:Adiponectin / Q000276:immunology / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055572:Ceramidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036904:Leukocyte Rolling / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D026361:Reactive Nitrogen Species / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism*
chemical_list: C499918:ADIPOQ protein, human; C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; C495540:CAV1 protein, human; D051242:Caveolin 1; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D054419:Receptors, Adiponectin; D014409:Tumor Necrosis Factor-alpha; D055572:Ceramidases
keywords: adipokines; endothelial cells; inflammation; sphingolipids; vascular system injuries