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Activation of Liver X Receptors Suppresses Inflammatory Gene Expressions and Transcriptional Corepressor Clearance in Rheumatoid Arthritis Fibroblast Like Synoviocytes

 Chong-Hyeon Yoon  ;  Yong-Jin Kwon  ;  Sang-Won Lee  ;  Yong-Beom Park  ;  Soo-Kon Lee  ;  Min-Chan Park 
 JOURNAL OF CLINICAL IMMUNOLOGY, Vol.33(1) : 190-199, 2013 
Journal Title
Issue Date
Arthritis, Rheumatoid/genetics ; Arthritis, Rheumatoid/immunology* ; Arthritis, Rheumatoid/pathology* ; Cell Line, Tumor ; Fibroblasts/immunology ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Gene Expression Regulation, Neoplastic/immunology* ; Humans ; Inflammation Mediators/antagonists & inhibitors* ; Liver X Receptors ; Orphan Nuclear Receptors/metabolism* ; Orphan Nuclear Receptors/physiology ; Repressor Proteins/antagonists & inhibitors* ; Repressor Proteins/metabolism ; Synovial Membrane/immunology ; Synovial Membrane/metabolism ; Synovial Membrane/pathology* ; Transcription, Genetic/immunology* ; Tumor Necrosis Factor-alpha/pharmacology
Rheumatoid arthritis ; liver X receptors ; GW3965 ; fibroblast like synoviocyte ; transcriptional corepressor
OBJECTIVES: 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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Yong Jin(권용진)
Park, Min Chan(박민찬) ORCID logo https://orcid.org/0000-0003-1189-7637
Park, Yong Beom(박용범)
Lee, Sang Won(이상원) ORCID logo https://orcid.org/0000-0002-8038-3341
Lee, Soo Kon(이수곤)
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