Suppression of inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 22( R)-hydroxycholesterol requires de novo protein synthesis in activated macrophages

• Published in: The Journal of steroid biochemistry and molecular biology 2005-12, Vol.97 (4), p.376-383
• Main Authors: Yasuda, Toshimichi, Kanno, Masamoto, Kawamoto, Masashi, Yuge, Osafumi, Ninomiya, Yuichi
• Format: Article
• Language: English
• Subjects: 22( R)-Hydroxycholesterol (22R-HC); Animals; Biological and medical sciences; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Line; Cells, Cultured; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - pharmacology; DNA - chemistry; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Glucocorticoids - metabolism; Hydroxycholesterols - pharmacology; Inflammation; Ligands; Lipopolysaccharides - chemistry; Lipopolysaccharides - metabolism; Liver X Receptors; Macrophage; Macrophage Activation; Macrophages - metabolism; Mice; Models, Statistical; NF-kappa B - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitrites - metabolism; Orphan Nuclear Receptors; Protein Binding; Proteins - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; RNA - chemistry; RNA - metabolism; RNA, Messenger - metabolism; Time Factors; Transcription Factor AP-1 - metabolism; Transcription, Genetic; Vertebrates: endocrinology
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2005.06.030

Liver X receptors (LXRs) play an important role in lipid metabolism. Recently, a role for these proteins was identified in suppressing the inflammatory response. However, it is not known whether the natural ligands of LXRs, e.g. 22( R)-hydroxycholesterol (22R-HC), can suppress the inflammatory response after the onset of inflammation. We demonstrate here that treatment of Lipopolysaccharide (LPS)-activated RAW264.7 macrophages with 22R-HC markedly suppressed nitric oxide (NO) production and inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression. Additionally, 22R-HC did not affect the DNA binding activity of NF-κB, AP-1 and C/EBP(s), important transcriptional factors for iNOS and COX-2 genes expression. Furthermore iNOS and COX-2 mRNA suppression by 22R-HC was diminished by cellular treatment with cycloheximide. These results suggest that 22R-HC suppresses the expression of iNOS and COX-2 genes through de novo protein synthesis of an unidentified protein in LPS-activated macrophages.