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15-deoxy-delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats
Y Kawahito1, M Kondo, Y Tsubouchi
1First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. kawahity@cam.hi-ho.ne.jp
Abstract:
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.
Insights
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is elevated in rheumatoid arthritis (RA) synovium. Its activation by ligands like 15d-PGJ(2) reduced arthritis severity and inflammation in rats.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors regulating adipocyte and monocyte differentiation.
- PPAR-gamma agonists influence macrophage activation and tumorigenesis.
- Rheumatoid arthritis (RA) involves chronic inflammation of synovial tissue.
Purpose of the Study:
- To investigate the expression and role of PPAR-gamma in rheumatoid arthritis (RA).
- To evaluate the therapeutic potential of PPAR-gamma ligands in an arthritis model.
Main Methods:
- Detected PPAR-gamma expression in synovial tissue from RA patients using immunohistochemistry.
- Activated PPAR-gamma in vitro using 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and troglitazone.
- Administered PPAR-gamma ligands to rats with adjuvant-induced arthritis.
Main Results:
- Markedly enhanced PPAR-gamma expression was found in macrophages within RA synovial tissue.
- PPAR-gamma activation induced apoptosis in RA synoviocytes in vitro.
- Ligand administration ameliorated arthritis in rats, suppressing pannus formation and inflammation.
- 15d-PGJ(2) demonstrated more potent anti-inflammatory effects than troglitazone.
Conclusions:
- PPAR-gamma is upregulated in RA synovial tissue and plays a role in inflammation.
- PPAR-gamma ligands, particularly 15d-PGJ(2), show promise for RA treatment.
- Targeting PPAR-gamma may offer a novel therapeutic strategy for rheumatoid arthritis.
