J Korean Rheum Assoc.  2010 Jun;17(2):153-161. 10.4078/jkra.2010.17.2.153.

Peroxisome Proliferator-activated Receptor-gamma Agonist Inhibits Pro-inflammatory Gene Expressions and Cellular Proliferation of Fibroblast Like Synoviocytes from Patients with Rheumatoid Arthritis by Down-regulation of NF-kappaB

• Kwon YJ
• Chung SJ
• Kim TY
• Park MC

• KMID: 2201960
• DOI: http://doi.org/10.4078/jkra.2010.17.2.153

Abstract

OBJECTIVE
This study investigated the effect of rosiglitazone, a synthetic peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, on pro-inflammatory gene expressions and cellular proliferation of fibroblast like synoviocyte (FLS) from patients with rheumatoid arthritis (RA), and to determine whether these actions are mediated by nuclear factor-kappaB (NF-B) down-regulation.
METHODS
Synovial tissues from patients with RA were obtained during total knee replacement surgery, and FLS were isolated. RA FLS were subsequently treated with 10 micrometer, 50 micrometer and 150 micrometer rosiglitazone with or without TNF-alpha (10 ng/mL) stimulation. FLS proliferation in response to rosiglitazone treatment was measured by MTT assay, and mRNA expressions of IL-1beta, IL-6, CCL-2, CCL-7, COX-2 and MMP-9 were determined by real-time quantitative RT-PCR. The effects of rosiglitazone on NF-kappaB activation were evaluated using electrophoretic mobility shift assay (EMSA).
RESULTS
Rosiglitazone treatment without TNF-alpha induced a dose-dependent reduction in mRNA expressions of IL-1beta, IL-6, CCL-2, CCL-7, COX-2 and MMP-9 from RA FLS. When TNF-alpha were treated with rosiglitazone, mRNA expressions of COX-2, MMP-9 were reduced dose-dependently. But mRNA expressions of IL-1beta, IL-6, CCL-2, CCL-7 were increased in 10 micrometer rosiglitazone with TNF-alpha and then decreased as the concentration of rosiglitazone increased. Rosiglitazone treatment also suppressed FLS proliferation in a dose-dependent manner, and EMSA showed decreased NF-kappaB expression with rosiglitazone treatment.
CONCLUSION
Rosiglitazone suppressed cellular proliferation and mRNA expressions of pro-inflammatory mediators by down-regulating the NF-kappaB signaling pathway in RA FLS. The outcomes suggest that activation of PPAR-gamma can be a novel therapeutic approach in RA.

Keyword

Rosiglitazone; Rheumatoid arthritis; Fibroblast-like synoviocytes; Pro-inflammatory mediators; NF-kappaB

MeSH Terms

Arthritis, Rheumatoid
Arthroplasty, Replacement, Knee
Cell Proliferation
Down-Regulation
Electrophoretic Mobility Shift Assay
Fibroblasts
Gene Expression
Humans
Interleukin-6
NF-kappa B
Peroxisomes
RNA, Messenger
Thiazolidinediones
Tumor Necrosis Factor-alpha
Interleukin-6
NF-kappa B
RNA, Messenger
Thiazolidinediones
Tumor Necrosis Factor-alpha

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