Functional changes in rheumatoid fibroblast-like synovial cells through activation of peroxisome proliferator-activated receptor gamma-mediated signalling pathway.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand dependent transcriptional factor known to be a regulator of adipogenesis. Recent studies have also shown that stimulation of PPARgamma inhibits the transcriptional activities of other nuclear factors and down-regulates proinflammatory cytokine synthesis in T cells and monocytes. We examined, in the present study, the functional significance of PPARgamma expressed in fibroblast-like synovial cells (FLS) isolated from patients with rheumatoid arthritis (RA). Incubation of FLS with a synthetic PPARgamma ligand, troglitazone, inhibited endogenous production of TNF-alpha, IL-6 and IL-8, as well as matrix metalloprotease-3 (MMP-3), without inducing apoptosis of the cells. The gelatinase activity of FLS culture media was also inhibited by troglitazone. Electrophoretic mobility shift assay (EMSA) showed a significant reduction in the DNA binding activity of NF-kappaB in troglitazone-treated FLS in response to TNF-alpha or IL-1beta. Moreover, long-term cultivation of FLS with troglitazone resulted in morphological changes with marked lipid accumulation in these cells. Our results show a negative regulatory function for PPARgamma on cytokine and MMP production together with inhibition of cytokine-mediated inflammatory responses in rheumatoid synovial cells. Our results also suggest that FLS could differentiate into adipocyte-like cells in the presence of proper stimulatory signals including PPARgamma.
Yamasaki
S
S
First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
Nakashima
T
T
Kawakami
A
A
Miyashita
T
T
Ida
H
H
Migita
K
K
Nakata
K
K
Eguchi
K
K
D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018093:Gelatinases / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013844:Thiazoles / Q000378:metabolism; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D002839:Chromans; D015850:Interleukin-6; D016209:Interleukin-8; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D018093:Gelatinases; D000077288:Troglitazone