Apolipoprotein e interrupts interleukin-1β signaling in vascular smooth muscle cells

Objectives - Apolipoprotein E ( apoE) exerts antiatherogenic effects but precise mechanisms remain unclear. We here investigated the effect of apoE on intracellular signaling by interleukin-1 beta( IL-1 beta), a proinflammatory cytokine present in atherosclerotic lesions. Methods and Results - IL-1 beta-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-kappa B and activating protein- 1 (AP-1) transactivation, suggesting that the interruption of IL-1 beta signaling occurs upstream of transcription factors. Studies in VSMCs overexpressing IL-1 beta signaling intermediates revealed that NF-kappa B 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-1 beta 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- 1 beta 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-1 beta and IL-18 signaling in VSMCs. This antiinflammatory effect represents a novel antiatherogenic activity of apoE.