• Li Chen, Qian Zhao, Xu-Liang Wang, Ran You, Yi-Hua Zhang, Hui Ji, and Yi-Sheng Lai.
• Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, PR China.
• Vascul. Pharmacol. 2011 Nov 1; 55 (5-6): 135-42.

AbstractNonsteroidal 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 μM) concentration-dependently decreased TNF-α-induced monocyte-endothelial interactions in both static and dynamic conditions whereas no effect was found after pretreatment with the COX-2 inhibitor celecoxib (30 μM), 5-LOX inhibitor zileuton (30 μM) 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-α-induced HUVECs. A further analysis indicated that ZLJ-6 attenuated TNF-α-induced nuclear translocation of NF-κB, IκB phosphorylation, IκB kinase β (IKKβ) activity, and subsequent NF-κB-DNA complex formation, suggesting that NF-κB pathway was involved in TNF-α-induced inflammation. However, ZLJ-6 did not affect TNF-α-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-α-induced monocyte-endothelial interactions and adhesion molecule (E-selectin, ICAM-1 and VCAM-1) expression and these effects were mediated by NF-κB signaling pathway rather than its primary pharmacological target COX-2 or 5-LOX.Copyright © 2011 Elsevier Inc. All rights reserved.

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