Hypoxia increases 25-hydroxycholesterol-induced interleukin-8 protein secretion in human macrophages.
Interleukin-8 (IL-8) is a chemotactic factor for T-lymphocytes and smooth muscle cells and may therefore have an important effect in atherogenesis. It is secreted from oxysterol-containing foam cells which have been found in hypoxic zones in atherosclerotic plaques. The aim of this study was to investigate the effect of hypoxia on the secretion of IL-8 by oxysterol-stimulated macrophages. Hypoxia enhances 25-hydroxycholesterol (25-OH-chol)-induced IL-8 secretion in human monocyte-derived macrophages. The effect is most pronounced when macrophages are incubated with low concentrations of 25-OH-chol. Both 25-OH-chol and hypoxia increases the intracellular level of the signalling molecule hydrogen peroxide (H(2)O(2)). This event coincided with an enhanced binding of the transcription factor c-jun to the IL-8 gene promoter and an increased IL-8 mRNA expression in hypoxic macrophages. These observations suggest that similar intracellular signalling pathways are used for both 25-OH-chol-induced IL-8 expression and hypoxia-induced IL-8 expression. Thus, hypoxia in atherosclerotic plaques may increase the secretion of IL-8 from oxysterol-containing foam cells, which subsequently may accelerate the progression of atherosclerosis.
Rydberg
Ellen Knutsen
EK
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg University, SE-41345 Göteborg, Sweden. ellen.rydberg@wlab.gu.se
Salomonsson
Linda
L
Hultén
Lillemor Mattsson
LM
Norén
Kristina
K
Bondjers
Göran
G
Wiklund
Olov
O
Björnheden
Tom
T
Ohlsson
Bertil G
BG
D025181:ATP Synthetase Complexes / Q000037:antagonists & inhibitors; D001161:Arteriosclerosis / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006888:Hydroxycholesterols / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D016209:Interleukin-8; D009840:Oligomycins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014810:Vitamin E; C007997:25-hydroxycholesterol; D006861:Hydrogen Peroxide; D025181:ATP Synthetase Complexes