Apolipoprotein E interrupts interleukin-1beta signaling in vascular smooth muscle cells.
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.
Kawamura
Akira
A
Department of Lipid Metabolism, Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Germany.
Baitsch
Daniel
D
Telgmann
Ralph
R
Feuerborn
Renata
R
Weissen-Plenz
Gabriele
G
Hagedorn
Claudia
C
Saku
Keijiro
K
Brand-Herrmann
Stefan-Martin
SM
von Eckardstein
Arnold
A
Assmann
Gerd
G
Nofer
Jerzy-Roch
JR
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
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