Weber K S, Draude G, Erl W, de Martin R, Weber C
Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians Universität, München, Germany.
Blood. 1999 Jun 1;93(11):3685-93.
Mobilization of nuclear factor-kappaB (NF-kappaB) activates transcription of genes encoding endothelial adhesion molecules and chemokines that contribute to monocyte infiltration critical in atherogenesis. Inhibition of NF-kappaB has been achieved by pharmacological and genetic approaches; however, monocyte interactions with activated endothelium in shear flow following gene transfer of the NF-kappaB inhibitor IkappaB-alpha have not been studied. We found that overexpression of IkappaB-alpha in endothelial cells using a recombinant adenovirus prevented tumor necrosis factor-alpha (TNF-alpha)-induced degradation of IkappaB-alpha and suppressed the upregulation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin mRNA and surface protein expression and the upregulation of transcripts for the chemokines monocyte chemoattractant protein 1 (MCP-1) and growth-related activity-alpha (GRO-alpha) by TNF-alpha. This was associated with a reduction in endothelial MCP-1 secretion and GRO-alpha immobilization. Adhesion assays under physiological shear flow conditions showed that firm arrest, spreading, and transmigration of monocytes on TNF-alpha-activated endothelium was markedly inhibited by IkappaB-alpha overexpression. Inhibition with monoclonal antibodies and peptide antagonists inferred that this was due to reduced expression of Ig integrin ligand as well as of chemokines specifically involved in these events. In contrast, rolling of monocytes was increased by IkappaB-alpha transfer and was partly mediated by P-selectin; however, it appeared to be unaffected by the inhibition of E-selectin induction. Thus, our data provide novel evidence that selective modulation of NF-kappaB by adenoviral transfer of IkappaB-alpha impairs the expression of multiple endothelial gene products required for subsequent monocyte arrest and emigration in shear flow and thus for monocyte infiltration in atherosclerotic plaques.
核因子-κB（NF-κB）的激活可启动编码内皮黏附分子和趋化因子的基因转录，这些分子有助于单核细胞浸润，而单核细胞浸润在动脉粥样硬化形成过程中至关重要。通过药理学和遗传学方法已实现对NF-κB的抑制；然而，在转染NF-κB抑制剂IκB-α基因后，单核细胞在剪切流中与活化内皮的相互作用尚未得到研究。我们发现，利用重组腺病毒在内皮细胞中过表达IκB-α可防止肿瘤坏死因子-α（TNF-α）诱导的IκB-α降解，并抑制血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）和E-选择素mRNA及表面蛋白表达的上调，以及TNF-α诱导的趋化因子单核细胞趋化蛋白1（MCP-1）和生长相关活性-α（GRO-α）转录本的上调。这与内皮MCP-1分泌减少和GRO-α固定化有关。生理剪切流条件下的黏附试验表明，IκB-α过表达可显著抑制单核细胞在TNF-α活化内皮上的牢固黏附、铺展和迁移。单克隆抗体和肽拮抗剂的抑制作用表明，这是由于Ig整合素配体以及这些事件中特异性涉及的趋化因子表达减少所致。相反，IκB-α转染可增加单核细胞的滚动，且部分由P-选择素介导；然而，它似乎不受E-选择素诱导抑制的影响。因此，我们的数据提供了新的证据，即通过腺病毒转染IκB-α对NF-κB进行选择性调节会损害后续单核细胞在剪切流中黏附及移出以及动脉粥样硬化斑块中单核细胞浸润所需的多种内皮基因产物的表达。
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