title: 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.
abstract: 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 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.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Xu-Liang
authors.initials: XL
authors.lastname: Wang
authors.forename: Ran
authors.initials: R
authors.lastname: You
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Yi-Sheng
authors.initials: YS
authors.lastname: Lai
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D019040:E-Selectin / Q000096:biosynthesis / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000378:metabolism
chemical_list: C541786:1-methyl-1,5-dihydro-2-amino-5-(4-(mesyl)benzylidene)-4H-imidazole-4-one; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D016861:Cyclooxygenase Inhibitors; D019040:E-Selectin; C573420:ICAM1 protein, human; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; C546936:SELE protein, human; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D001094:Arachidonate 5-Lipoxygenase