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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Arachidonate 5-Lipoxygenase / chemistry
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Arachidonate 5-Lipoxygenase / metabolism
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Cell Adhesion / drug effects
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Cell Adhesion Molecules / biosynthesis*
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Cell Line
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Cell Membrane / drug effects*
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Cell Membrane / metabolism
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cells, Cultured
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Cyclooxygenase Inhibitors / pharmacology*
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E-Selectin / biosynthesis
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E-Selectin / metabolism
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects*
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Endothelium, Vascular / immunology
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Endothelium, Vascular / metabolism
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / immunology
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Imidazoles / pharmacology*
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intercellular Adhesion Molecule-1 / metabolism
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Lipoxygenase Inhibitors / pharmacology*
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Monocytes / drug effects*
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Monocytes / immunology
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Protein Transport / drug effects
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Signal Transduction / drug effects
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Sulfones / pharmacology*
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Tumor Necrosis Factor-alpha / metabolism
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Vascular Cell Adhesion Molecule-1 / biosynthesis
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Vascular Cell Adhesion Molecule-1 / metabolism
Substances
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1-methyl-1,5-dihydro-2-amino-5-(4-(mesyl)benzylidene)-4H-imidazole-4-one
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Anti-Inflammatory Agents, Non-Steroidal
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Cell Adhesion Molecules
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Cyclooxygenase Inhibitors
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E-Selectin
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ICAM1 protein, human
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Imidazoles
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Lipoxygenase Inhibitors
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NF-kappa B
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SELE protein, human
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Sulfones
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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Arachidonate 5-Lipoxygenase