Ryoji Yamada

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-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.

Auranofin inhibits interleukin-1β-induced transcript of cyclooxygenase-2 on cultured human synoviocytes

The aim of this study was to characterize the effects of auranofin (2,3,4,6-tetra-O-acetyl-l-thio-beta-D-gluco-pyranosato-S) on cyclooxygenase expression and prostaglandin E(2) synthesis on cultured human synovial fibroblast-like cells (synoviocytes). Synoviocytes were treated with auranofin in the presence or absence of interleukin-1beta. Cultured supernatants were harvested for prostaglandin E(2) synthesis. Cyclooxygenase-1 and -2 expression was analyzed with Western and Northern blotting. Translocation of nuclear factor-kappa B p65 was determined by immunostaining. Cytotoxicity was measured with 51Cr release assay. Auranofin attenuated interleukin-1beta-induced prostaglandin E(2) production of the cells in a dose-dependent fashion. Auranofin selectively suppressed interleukin-1beta-induced cyclooxygenase-2 mRNA and protein expression of the cells without alteration of cyclooxygenase-1 expression. Also, auranofin interfered with interleukin-1beta-induced translocation of nuclear factor-kappa B. These inhibitory effects did not originate in the cytotoxicity of the agent. Our data indicate that auranofin inhibits interleukin-1beta-induced prostaglandin E(2) synthesis and cyclooxygenase-2 expression via suppression of nuclear factor-kappa B activation on synoviocytes.

Preferential inhibition of cyclooxygenase-2 by meloxicam in human rheumatoid synoviocytes

The aim of this study was to evaluate the anti-inflammatory effect of 4-hydroxy-2-methyl-N-[5-methyl-2-thiazolyl]-2H-1, 2-benzothiazine-3-carboxamide-1,1-dioxide (meloxicam) using cultured rheumatoid synovial fibroblast-like cells (synoviocytes). Synoviocytes were treated with meloxicam in the presence or absence of interleukin-1beta. Meloxicam had no effect on both cyclooxygenase-1 and -2 expression as determined by Western blot analysis, immunohistochemical staining, and reverse transcription polymerase chain reaction (RT-PCR). Even the lower doses of meloxicam inhibited cyclooxygenase-2 activity, but only the higher doses of meloxicam inhibited cyclooxygenase-1 activity as determined by prostaglandin E(2) synthesis assay. So meloxicam had a preferential inhibitory effect of cyclooxygenase-2 relative to cyclooxygenase-1 on cultured rheumatoid synoviocytes without affecting cyclooxygenase expression. On the other hand, indomethacin had no selectivity and dexamethasone inhibited the expression of cyclooxygenase-2. Our data indicate that clinical efficacy and safety of meloxicam for rheumatoid arthritis may result from its preferential inhibition of cyclooxygenase-2 activity relative to cyclooxygenase-1 on rheumatoid synoviocytes.

ACTH expression in synovium of patients with rheumatoid arthritis and Lewis rats with adjuvant arthritis.

Abstract Adrenocorticotropic hormone (ACTH) and another pro-opiomelanocortin-derived neuropeptide, β-endorphin (β-End), are stimulated by corticotropin-releasing hormone (CRH) at the anterior pituitary. CRH and β-End have predominantly proinflammatory effects in peripheral inflammatory sites. We have supposed that inflammatory stimuli develop ACTH as well as β-End. In this study, we investigated the expression of ACTH in inflamed synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and at inflammatory joints with adjuvant-induced arthritis (AA) in female Lewis (LEW/N) rats. The expression of ACTH immunostaining was significantly greater in synovium of RA patients than in that of OA patients (P < 0.0001), and correlated with the extent of inflammatory mononuclear cell infiltration. Extensive and intense intracellular ACTH immunostaining, which correlated with the advance in arthritis score, was observed in the synovial lining layer, inflammatory mononuclear cells, and fibroblast-like cells of synovium and chondrocytes in LEW/N rats with AA. In addition, we performed double immunostaining of the same sections from arthritic joints in rats with anti-ACTH and anti-CRH antibodies. ACTH and CRH colocalized in inflammatory mononuclear cells and fibroblast-like cells. ACTH may play a role in the pathogenesis of RA as well as CRH.