15-deoxy-delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-gamma agonists are also negative regulators of macrophage activation and have modulatory effects on tumorige...

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Bibliographic Details
Published in:The Journal of clinical investigation 2000-07, Vol.106 (2), p.189-197
Main Authors: Kawahito, Y, Kondo, M, Tsubouchi, Y, Hashiramoto, A, Bishop-Bailey, D, Inoue, K, Kohno, M, Yamada, R, Hla, T, Sano, H
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Arthritis - drug therapy
Arthritis, Experimental - drug therapy
Arthritis, Rheumatoid - drug therapy
Cells, Cultured
Chromans - pharmacology
Female
Humans
Ligands
Osteoarthritis - drug therapy
Prostaglandin D2 - analogs & derivatives
Prostaglandin D2 - pharmacology
Prostaglandin D2 - therapeutic use
Rats
Rats, Inbred Lew
Receptors, Cytoplasmic and Nuclear - drug effects
Receptors, Cytoplasmic and Nuclear - genetics
RNA, Messenger - isolation & purification
Synovial Membrane - cytology
Synovial Membrane - drug effects
Thiazoles - pharmacology
Thiazolidinediones
Tissue Distribution
Transcription Factors - drug effects
Transcription Factors - genetics
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Summary:Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-gamma agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-gamma in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-gamma in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-gamma by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and the synthetic PPAR-gamma ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-gamma ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ(2) were more potent than troglitazone. These findings suggest that PPAR-gamma may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ(2), may be useful in the treatment of RA.
ISSN:0021-9738
DOI:10.1172/JCI9652