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首页> 外文期刊>Vascular pharmacology >ZLJ-6, a novel COX/5-LOX inhibitor, attenuates TNF-a-induced endothelial E-selectin, ICAM-1 and VCAM-1 expression and monocyte-endothelial interactions via a COX/5-LOX-independent mechanism
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ZLJ-6, a novel COX/5-LOX inhibitor, attenuates TNF-a-induced endothelial E-selectin, ICAM-1 and VCAM-1 expression and monocyte-endothelial interactions via a COX/5-LOX-independent mechanism

机译：ZLJ-6是一种新型的COX / 5-LOX抑制剂，通过独立于COX / 5-LOX的机制减弱TNF-a诱导的内皮细胞E-选择素，ICAM-1和VCAM-1的表达以及单核细胞-内皮细胞的相互作用

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are previously found to possess prostaglandin and leukotriene-independent anti-inflammatory effect. The aim of the present study was to investigate the prostaglandin and leukotriene-independent anti-inflammatory effect of an imidazolone COX/5-LOX inhibitor ZLJ-6 and the underlying mechanism. Pretreatment human umbilical vein endothelial cells (HUVECs) with ZLJ-6 (3,10 and 30 uM) concentration-dependently decreased TNF-a-induced monocyte-endothelial interactions in both static and dynamic conditions whereas no effect was found after pretreatment with the COX-2 inhibitor celecoxib (30 MUM), 5-LOX inhibitor zileuton (30 uM) and the combination of them. ZLJ-6 also attenuated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cytoadhesion molecule-1 (VCAM-1) on TNF-a-induced HUVECs. A further analysis indicated that ZLJ-6 attenuated TNF-a-induced nuclear translocation of NF-kappaB, IkkappaB phosphorylation, IkappaB kinase beta (IKKbeta) activity, and subsequent NF-kappaB-DNA complex formation, suggesting that NF-kappaB pathway was involved in TNF-a-induced inflammation. However, ZLJ-6 did not affect TNF-a-induced extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 phosphorylation. Taken together, our results indicated that ZLJ-6 potently inhibited TNF-a-induced monocyte-endothelial interactions and adhesion molecule (E-selectin, ICAM-1 and VCAM-1) expression and these effects were mediated by NF-kB signaling pathway rather than its primary pharmacological target COX-2 or 5-LOX.
机译：先前发现非甾体抗炎药（NSAIDs）具有前列腺素和白三烯非依赖性抗炎作用。本研究的目的是研究咪唑酮COX / 5-LOX抑制剂ZLJ-6的前列腺素和白三烯非依赖性抗炎作用及其潜在机制。用ZLJ-6（3,10和30 uM）浓度预处理的人脐静脉内皮细胞（HUVEC）在静态和动态条件下均会降低TNF-a诱导的单核细胞-内皮细胞相互作用，而用COX预处理后未发现任何作用-2抑制剂塞来昔布（30 MUM），5-LOX抑制剂齐留通（30 uM）及其组合。 ZLJ-6还减弱了TNF-α诱导的HUVEC上E-选择蛋白，细胞间粘附分子1（ICAM-1）和血管细胞粘附分子1（VCAM-1）的表达。进一步的分析表明ZLJ-6减弱了TNF-a诱导的NF-kappaB的核易位，IkkappaB磷酸化，IkappaB激酶beta（IKKbeta）活性以及随后的NF-kappaB-DNA复合物的形成，表明涉及到NF-kappaB途径。在TNF-α诱导的炎症中。但是，ZLJ-6不会影响TNF-a诱导的细胞外信号调节激酶（ERK1 / 2），c-Jun N端激酶（JNK）和p38磷酸化。综上所述，我们的结果表明ZLJ-6有效抑制TNF-a诱导的单核细胞-内皮相互作用和粘附分子（E-选择素，ICAM-1和VCAM-1）的表达，而这些作用是由NF-kB信号通路介导的。而不是其主要药理目标COX-2或5-LOX。

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