title: Apolipoprotein E interrupts interleukin-1beta signaling in vascular smooth muscle cells.
abstract: OBJECTIVE
  Apolipoprotein E (apoE) exerts antiatherogenic effects but precise mechanisms remain unclear. We here investigated the effect of apoE on intracellular signaling by interleukin-1beta (IL-1beta), a proinflammatory cytokine present in atherosclerotic lesions.
  
  
  RESULTS
  IL-1beta-induced expression and activation of inducible nitric oxide synthase and cyclooxygenase-2 were inhibited by apoE in vascular smooth muscle cells (VSMCs). These inhibitory effects were linked to the suppression of both NF-kappaB and activating protein-1 (AP-1) transactivation, suggesting that the interruption of IL-1beta signaling occurs upstream of transcription factors. Studies in VSMCs overexpressing IL-1beta signaling intermediates revealed that NF-kappaB transactivation was inhibited by apoE in MyD88- and IRAK1- but not in TRAF6-transfected cells. Furthermore, apoE prevented IRAK1 phosphorylation and IRAK1-TRAF6 but not MyD88-IRAK1 complex formation. Inhibitory effects of apoE on IL-1beta signaling were abolished after silencing LDL receptor-related protein-1 (LRP1) expression with siRNA. In addition, inhibitors of adenylyl cyclase and protein kinase A (PKA) restored IL-1beta signaling in apoE-treated VSMCs, whereas apoE stimulated PKA activity. ApoE inhibited VSMC activation in response to IL-18 but not to tumor necrosis factor-alpha or polyinosinic:polycytidylic acid.
  
  
  CONCLUSIONS
  ApoE targets IRAK-1 activation and thereby interrupts IL-1beta and IL-18 signaling in VSMCs. This antiinflammatory effect represents a novel antiatherogenic activity of apoE.
authors.affiliation: Department of Lipid Metabolism, Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Germany.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawamura
authors.forename: Daniel
authors.initials: D
authors.lastname: Baitsch
authors.forename: Ralph
authors.initials: R
authors.lastname: Telgmann
authors.forename: Renata
authors.initials: R
authors.lastname: Feuerborn
authors.forename: Gabriele
authors.initials: G
authors.lastname: Weissen-Plenz
authors.forename: Claudia
authors.initials: C
authors.lastname: Hagedorn
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand-Herrmann
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: Gerd
authors.initials: G
authors.lastname: Assmann
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism / Q000494:pharmacology*; D050197:Atherosclerosis / Q000503:physiopathology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D012680:Sensitivity and Specificity; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D053583:Interleukin-1beta; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases