25-hydroxycholesterol induces lipopolysaccharide-tolerance and decreases alipopolysaccharide-induced TNF-alpha secretion in macrophages

Several different oxysterols are formed when LDL is oxidized. The role of o xysterols in the inflammatory process in the atherosclerotic plaque is not totally elucidated. In this study we have investigated the effect of four d ifferent oxysterols on an LPS-induced TNF-alpha secretion in human macropha ges. Cultured human macrophages were incubated with 7-keto-, 7 beta -hydrox y-, 27-hydroxy- and 25-hydroxycholesterol for 24 h before exposure to endot oxin (LPS) for 3 h. All oxysterols, except 7-ketocholesterol, significantly decreased an LPS-induced TNF-alpha secretion. The most pronounced effect w as obtained with 25-hydroxycholesterol, where the TNF-alpha secretion was r educed to 8%. This decreased effect was also found on the TNF-alpha mRNA le vel. The decreased LPS-induced TNF-alpha secretion coincided with an increa sed binding of the transcription factors Sp1 and Sp3 to the TNF-alpha promo ter. In vitro studies of the TNF-alpha promoter suggests possible interacti ons between Sp1 and Sp3 and the NF-kappaB transcription factor complex that might affect the transcriptional initiation. (C) 2001 Elsevier Science Ire land Ltd. All rights reserved.