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 1

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Immunostaining for PPAR-γ in synovial tissues from RA and OA. (a–c, e) S...
Immunostaining for PPAR-γ in synovial tissues from RA and OA. (a–c, e) Synovial tissues from RA. (d) Synovial tissues from OA. Synovial tissue sections were stained with goat anti-PPAR-γ (a, c, d) antibodies and a normal goat IgG (b). Tissues seen in a, b, and c are derived from different patients. Positive immunostaining was indicated by brownish deposits. In double immunostaining for macrophage and PPAR-γ (e), sections were stained with anti–PPAR-γ antibody using alkaline phosphatase method (red deposits) and anti-human macrophage using antibody peroxidase method (brownish-black deposits). Double-positive staining cells were indicated by black-red deposits. Counter staining was done with 0.5% light-green SF yellowish. ×100 (a–d); ×200 (e). SL, synovial lining cell; BV, blood vessel; M, macrophage; F, fibroblast.