Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase.
Arachidonate 15-lipoxygenase (arachidonate:oxygen 15-oxidoreductase, EC 1.13.11.33) is a lipid-peroxidating enzyme that is implicated in oxidizing low density lipoprotein to its atherogenic form. Monocyte/macrophage 15-lipoxygenase is present in human atherosclerotic lesions. To pursue a basis for induction of the enzyme, which is not present in blood monocytes, the ability of relevant cytokines to regulate its expression was investigated. Interleukin 4 (IL-4), among 16 factors tested, specifically induced 15-lipoxygenase mRNA and protein in cultured human monocytes. Interferon gamma and hydrocortisone inhibited this induction. High-performance liquid chromatography analysis of lipid extracts from IL-4-treated monocytes detected 15-lipoxygenase products esterified to the cellular membrane lipids, indicating enzymatic action on endogenous substrates. Stimulation of IL-4-treated monocytes with calcium ionophore or opsonized zymosan A enhanced the formation of 15-lipoxygenase products. These data identify IL-4 and interferon gamma as physiological regulators of lipoxygenase expression and suggest an important link between 15-lipoxygenase function and the immune/inflammatory response in atherosclerosis as well as other diseases.
Conrad
D J
DJ
Cardiovascular Research Institute, University of California, San Francisco 94143-0911.
Kuhn
H
H
Mulkins
M
M
Highland
E
E
Sigal
E
E
D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D015152:Blotting, Northern; D016207:Cytokines / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology*; D007371:Interferon-gamma / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008563:Membrane Lipids / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics
D016207:Cytokines; D006893:Hydroxyeicosatetraenoic Acids; D008563:Membrane Lipids; D012333:RNA, Messenger; D015847:Interleukin-4; D016718:Arachidonic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D007371:Interferon-gamma; D001093:Arachidonate 15-Lipoxygenase