Apolipoprotein E interrupts interleukin-1beta signaling in vascular smooth muscle cells

Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1610-7. doi: 10.1161/ATVBAHA.106.129957. Epub 2007 May 17.

Abstract

Objectives: 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.

Methods and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / metabolism
  • Apolipoproteins E / pharmacology*
  • Atherosclerosis / physiopathology
  • Cells, Cultured
  • Cyclooxygenase 2 / metabolism*
  • Interleukin-1 Receptor-Associated Kinases / drug effects
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Interleukin-1beta / metabolism
  • Interleukin-1beta / pharmacology*
  • Muscle, Smooth, Vascular / cytology*
  • Muscle, Smooth, Vascular / metabolism
  • Nitric Oxide Synthase Type II / drug effects
  • Nitric Oxide Synthase Type II / metabolism
  • Phosphorylation
  • Rats
  • Sensitivity and Specificity
  • Signal Transduction

Substances

  • Apolipoproteins E
  • Interleukin-1beta
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • IRAK1 protein, human
  • Interleukin-1 Receptor-Associated Kinases