title: Suppression of inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 22(R)-hydroxycholesterol requires de novo protein synthesis in activated macrophages.
abstract: 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-kappaB, 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.
authors.affiliation: Department of Anesthesiology and Critical Care, Hiroshima University, 1-2-3, kasumi, Hiroshima 734-8551, Japan.
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yasuda
authors.forename: Masamoto
authors.initials: M
authors.lastname: Kanno
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Osafumi
authors.initials: O
authors.lastname: Yuge
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ninomiya
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000378:metabolism; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007249:Inflammation; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D000071518:Liver X Receptors; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D015233:Models, Statistical; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D016861:Cyclooxygenase Inhibitors; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D006888:Hydroxycholesterols; D008024:Ligands; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D016328:NF-kappa B; D009573:Nitrites; D057093:Orphan Nuclear Receptors; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018808:Transcription Factor AP-1; C003585:22-hydroxycholesterol; D009569:Nitric Oxide; D012313:RNA; D004247:DNA; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2