Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1610-7. Epub 2007 May 17.

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

Kawamura, A., Baitsch, D., Telgmann, R., Feuerborn, R., Weissen-Plenz, G., Hagedorn, C., Saku, K., Brand-Herrmann, S. M., von Eckardstein, A., Assmann, G., Nofer, J. R.,
--- - Department of Lipid Metabolism, Leibniz-Institut fur Arterioskleroseforschung an der Universitat Munster, Germany.
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.
PMID: 17510469External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DD IRAK1 Link Myd88 Co-immunoprecipitation Rat thoracic aortas derived vascular smooth muscle cell Not specified 1-710 Not specified 1-306 17510469
(Link: click this icon to show interactions only between the two corresponding DDs)