title: Activation of liver X receptors suppresses inflammatory gene expressions and transcriptional corepressor clearance in rheumatoid arthritis fibroblast like synoviocytes.
abstract: OBJECTIVE
  Liver X receptors (LXR) are nuclear receptors that play important roles in lipid metabolism and transport. LXR also suppress inflammatory responses in macrophages through a unique mechanism of transrepression. This study was performed to investigate whether the synthetic LXR agonist GW3965 can modulate the inflammatory status of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and to identify the mechanism for their effect.
  
  
  METHODS
  RA FLS were treated with 0.1 and 1 μM of GW3965, a synthetic LXR agonist. The mRNA expressions of pro-inflammatory mediators were measured using quantitative real-time PCR. Apoptotic cell death of RA FLS was assessed using TUNEL assay and determination of caspase-3 activity by a colorimetric assay. The levels of transcriptional corepressors including NCoR and SMRT were determined using western blot analyses.
  
  
  RESULTS
  Treatment of RA FLS with GW3965 induced dose-dependent reductions in mRNA expression of pro-inflammatory mediators (IL-1β, IL-6, MMP-9, CCL-2, CCL-7, and COX-2). However, treatment with GW3965 at the concentration selected for this study had no effect on apoptosis of RA FLS. Decreased productions of NCoR and SMRT by LPS stimulation was attenuated by GW3965 treatment.
  
  
  CONCLUSIONS
  GW3965 treatment suppressed mRNA expressions of pro-inflammatory mediators from RA FLS and inhibited the clearance of transcriptional corepressors. These data suggest that LXR activation can be used as a therapeutic approach to reduce the synovial inflammation in RA.
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Chong-Hyeon
authors.initials: CH
authors.lastname: Yoon
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Kwon
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Yong-Beom
authors.initials: YB
authors.lastname: Park
authors.forename: Soo-Kon
authors.initials: SK
authors.lastname: Lee
authors.forename: Min-Chan
authors.initials: MC
authors.lastname: Park
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018836:Inflammation Mediators; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha