ZLJ-6, a novel COX/5-LOX inhibitor, attenuates TNF-α-induced endothelial E-selectin, ICAM-1 and VCAM-1 expression and monocyte-endothelial interactions via a COX/5-LOX-independent mechanism

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