Weber C, Erl W, Pietsch A, Weber P C
Institut für Prophylaxe der Kreislaufkrankheiten, Ludwig-Maximilians-Universität, München, Germany.
Circulation. 1995 Apr 1;91(7):1914-7. doi: 10.1161/01.cir.91.7.1914.
The induction of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin by tumor necrosis factor-alpha (TNF) is mediated by mobilization of the transcription factor nuclear factor-kappa B (NF-kappa B). Since salicylates have been reported to inhibit NF-kappa B activation by preventing the degradation of its inhibitor I kappa B, we studied a potential inhibition of this pathway by acetylsalicylate (aspirin) in human umbilical vein endothelial cells (HUVECs).
Gel-shift analyses demonstrated dose-dependent inhibition of TNF-induced NF-kappa B mobilization by aspirin at concentrations ranging from 1 to 10 mmol/L. Induction of VCAM-1 and E-selectin surface expression by TNF was dose-dependently reduced by aspirin over the same range, while induction of intercellular adhesion molecule-1 (ICAM-1) was hardly affected. Aspirin appeared to prevent VCAM-1 transcription, since it dose-dependently inhibited induction of VCAM-1 mRNA by TNF. As a functional consequence, adhesion of U937 monocytes to TNF-stimulated HUVECs was markedly reduced by aspirin due to suppression of VCAM-1 and E-selectin upregulation. These effects of aspirin were not related to the inhibition of cyclooxygenase activity, since indomethacin was ineffective.
Our data suggest that aspirin inhibits NF-kappa B mobilization, induction of VCAM-1 and E-selectin, and subsequent monocyte adhesion in endothelial cells stimulated by TNF, thereby providing an additional mechanism for therapeutic effects of aspirin.
肿瘤坏死因子-α（TNF）诱导血管细胞黏附分子-1（VCAM-1）和E-选择素是由转录因子核因子-κB（NF-κB）的激活介导的。由于已有报道称水杨酸盐可通过阻止其抑制剂IκB的降解来抑制NF-κB的激活，因此我们研究了乙酰水杨酸（阿司匹林）对人脐静脉内皮细胞（HUVECs）中该信号通路的潜在抑制作用。
凝胶迁移分析表明，阿司匹林在1至10 mmol/L的浓度范围内对TNF诱导的NF-κB激活具有剂量依赖性抑制作用。在相同浓度范围内，阿司匹林可剂量依赖性地降低TNF诱导的VCAM-1和E-选择素表面表达，而对细胞间黏附分子-1（ICAM-1）的诱导几乎没有影响。阿司匹林似乎可阻止VCAM-1转录，因为它能剂量依赖性地抑制TNF诱导的VCAM-1 mRNA表达。作为功能结果，由于抑制了VCAM-1和E-选择素的上调，阿司匹林显著降低了U937单核细胞与TNF刺激的HUVECs的黏附。阿司匹林的这些作用与环氧化酶活性的抑制无关，因为吲哚美辛无效。
我们的数据表明，阿司匹林可抑制TNF刺激的内皮细胞中NF-κB的激活、VCAM-1和E-选择素的诱导以及随后的单核细胞黏附，从而为阿司匹林的治疗作用提供了另一种机制。
