25-Hydroxycholesterol, 7beta-hydroxycholesterol and 7-ketocholesterol upregulate interleukin-8 expression independently of Toll-like receptor 1, 2, 4 or 6 signalling in human macrophages.
Recent studies have shown that Toll-like receptor (TLR)- signalling contributes significantly to the inflammatory events of atherosclerosis. As products of cholesterol oxidation (oxysterols) accumulate within atherosclerotic plaque and have been proposed to contribute to inflammatory signalling in the diseased artery, we investigated the potential of 7-ketocholesterol (7-KC), 7beta-hydroxycholesterol (7beta-HC) and 25-hydroxycholesterol (25-HC) to stimulate inflammatory signalling via the lipid-recognising TLRs 1, 2, 4 and 6. Each oxysterol stimulated secretion of the inflammatory chemokine interleukin-8 (IL-8), but not IkappaBalpha degradation or tumour necrosis factor-alpha release from monocytic THP-1 cells. Transfection of TLR-deficient HEK-293 cells with TLRs 1, 2, 4 or 6 did not increase sensitivity to the tested oxysterols. Moreover, blockade of TLR2 or TLR4 with specific inhibitors did not reduce 25-hydroxycholesterol (25-HC) induced IL-8 release from THP-1 cells. We conclude that although the oxysterols examined in this study may contribute to increased expression of certain inflammatory genes, this occurs by mechanisms independent of TLR signalling.
Erridge
Clett
C
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. clett.erridge@strath.ac.uk
Webb
David J
DJ
Spickett
Corinne M
CM
D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism*; D007653:Ketocholesterols / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
D006888:Hydroxycholesterols; D016209:Interleukin-8; D007653:Ketocholesterols; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495368:TLR6 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; C011724:cholest-5-en-3 beta,7 alpha-diol; C007997:25-hydroxycholesterol; C003001:7-ketocholesterol