15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats
Yutaka Kawahito, … , Timothy Hla, Hajime Sano
Yutaka Kawahito, … , Timothy Hla, Hajime Sano
Published January 15, 2000
Citation Information: J Clin Invest. 2000;106(2):189-197. https://doi.org/10.1172/JCI9652.
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Article

15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats

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-γ 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-γ in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-γ in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-γ by 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and the synthetic PPAR-γ ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-γ ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ2 were more potent than troglitazone. These findings suggest that PPAR-γ may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ2, may be useful in the treatment of RA.

Authors

Yutaka Kawahito, Motoharu Kondo, Yasunori Tsubouchi, Akira Hashiramoto, David Bishop-Bailey, Ken-ichiro Inoue, Masataka Kohno, Ryoji Yamada, Timothy Hla, Hajime Sano

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Figure 7

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Photographic and histological features of the hindlimb in AIA treated wi...
Photographic and histological features of the hindlimb in AIA treated with 15d-PGJ2 or PBS. (a and c) Samples from a representative rat treated with 15d-PGJ2 in AIA. (b and d) Samples from a PBS-treated rat in AIA. Joint swelling of the foot in AIA was clearly reduced with 15d-PGJ2 administration at a dose of 1 mg/kg/d, at day 18 (a), compared with control (b). H&E staining of the foot joint also revealed a marked decrease of synovial inflammatory cell infiltrate and synovial lining hyperplasia (c). In contrast, hindlimbs treated with PBS revealed typical features of arthritis such as massive inflammatory cell infiltrate, pannus, and bone destruction (d). Similar findings of photographic and histological features were observed in all rats of each group. (c) ×25; (d) ×50.