title: Inhibition of 5-lipoxygenase blocks IL-1 beta-induced vascular adhesion molecule-1 gene expression in human endothelial cells.
abstract: Inflammation is characterized by the recruitment of leukocytes and their subsequent migration from the vasculature into the tissue, where they often cause severe damage. Endothelial cells play a major role in this cascade by expressing cell surface adhesion molecules, such as VCAM-1 and ICAM-1, and chemokines, in response to cytokines. Many of these genes are under the control of inflammatory response transcription factors such as nuclear factor (NF)-kappa B. In this study, we examined the effects of 5-lipoxygenase inhibitors (nordihydroguaiaretic acid and AA861) on IL-1 beta-induced VCAM-1 gene expression in HUVECs. We demonstrated that 5-lipoxygenase inhibitors, but not cyclooxygenase inhibitors, block IL-1 beta-induced VCAM-1 cell surface expression and promoter activity. In transiently transfected HUVECs, NF-kappa B-dependent gene expression was inhibited by 5-lipoxygenase inhibitors. These inhibitors did not block IL-1 beta-induced nuclear translocation of NF-kappa B, inhibitor of kappa B-alpha proteolytic degradation, or significantly reduce phosphorylation of p65. These studies indicate that inhibition of 5-lipoxygenase blocks cytokine-induced VCAM-1 gene expression by reducing the functional activity of NF-kappa B/Rel proteins in HUVECs.
authors.affiliation: Department of Biology, Tanabe Research Laboratories, San Diego CA 92121, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: K A
authors.initials: KA
authors.lastname: Felts
authors.forename: G C
authors.initials: GC
authors.lastname: Parry
authors.forename: L M
authors.initials: LM
authors.lastname: Armacost
authors.forename: R R
authors.initials: RR
authors.lastname: Cobb
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics*
chemical_list: D016227:Benzoquinones; D007375:Interleukin-1; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D009637:Masoprocol; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone