Inhibition of 5-lipoxygenase blocks IL-1 beta-induced vascular adhesion molecule-1 gene expression in human endothelial cells.
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.
Lee
S
S
Department of Biology, Tanabe Research Laboratories, San Diego CA 92121, USA.
Felts
K A
KA
Parry
G C
GC
Armacost
L M
LM
Cobb
R R
RR
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*
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