Kawamura Akira, Baitsch Daniel, Telgmann Ralph, Feuerborn Renata, Weissen-Plenz Gabriele, Hagedorn Claudia, Saku Keijiro, Brand-Herrmann Stefan-Martin, von Eckardstein Arnold, Assmann Gerd, Nofer Jerzy-Roch
Department of Lipid Metabolism, Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Germany.
Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1610-7. doi: 10.1161/ATVBAHA.106.129957. Epub 2007 May 17.
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.
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.
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.
载脂蛋白E（apoE）具有抗动脉粥样硬化作用，但其确切机制尚不清楚。我们在此研究了apoE对白细胞介素-1β（IL-1β）细胞内信号传导的影响，IL-1β是一种存在于动脉粥样硬化病变中的促炎细胞因子。
在血管平滑肌细胞（VSMC）中，apoE抑制IL-1β诱导的诱导型一氧化氮合酶和环氧化酶-2的表达及激活。这些抑制作用与核因子κB（NF-κB）和活化蛋白-1（AP-1）反式激活的抑制有关，提示IL-1β信号传导的中断发生在转录因子的上游。对过表达IL-1β信号传导中间体的VSMC研究显示，在MyD88和IRAK1转染的细胞中，apoE抑制NF-κB反式激活，但在TRAF6转染的细胞中则不然。此外，apoE可阻止IRAK1磷酸化以及IRAK1-TRAF6复合物形成，但不影响MyD88-IRAK1复合物形成。用小干扰RNA（siRNA）沉默低密度脂蛋白受体相关蛋白-1（LRP1）表达后，apoE对IL-1β信号传导的抑制作用消失。此外，腺苷酸环化酶抑制剂和蛋白激酶A（PKA）可恢复apoE处理的VSMC中的IL-1β信号传导，而apoE可刺激PKA活性。apoE抑制VSMC对IL-18而非肿瘤坏死因子-α或聚肌苷酸:聚胞苷酸的激活反应。
apoE靶向IRAK-1激活，从而中断VSMC中的IL-1β和IL-18信号传导。这种抗炎作用代表了apoE一种新的抗动脉粥样硬化活性。
