Activation of Liver X Receptors Suppresses Inflammatory Gene Expressions and Transcriptional Corepressor Clearance in Rheumatoid Arthritis Fibroblast Like Synoviocytes
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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.
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.
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.
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.
KeywordsRheumatoid arthritis liver X receptors GW3965 fibroblast like synoviocyte transcriptional corepressor
This study was supported by a grant from the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A100134) and a grant from the Yonsei University Research Fund [6-2010-0124].
We are grateful to Tae-Yeon Kim and Eunji Lee, Gangnam Severance Hospital Biomedical Research Center, for technical assistance, and to J. L. Collins, PhD, GlaxoSmithKline R&D, USA, for providing the GW3965 compound. GlaxoSmithKline had no role in study design, data collection, data analysis, data interpretation or manuscript preparation.
Conflict of Interest
The authors declare that they have no conflict of interest.
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