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Involvement of Prostaglandin E₂ in Interleukin-1-Induced Parathyroid Hormone-Related Peptide Production in Synovial Fibroblasts of Patients with Rheumatoid Arthritis

Department of Nutrition, Tokyo Metropolitan Institute of Gerontology (T.Y., A.S., Y.K.), Tokyo 173-0015, Japan; Sakamoto Clinic (H.S.), Kagoshima 899-73, Japan; Department of Internal Medicine (T.H.), Department of Orthopaedic Surgery (S.Y.), Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan; and Department of Orthopaedic Surgery, School of Medicine, University of Tokyo (H.O.), Tokyo 113-8655

Address all correspondence and requests for reprints to: Yasuko Koshihara, Ph.D., Department of Nutrition, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo, 173-0015, Japan. E-mail: ykoshi{at}tmig.or.jp

Abstract

Synovial fibroblasts, established in culture from patients with RA, were treated with proinflammatory cytokines and prostaglandin E₂ (PGE₂) for 24 h. These cells enhanced the production and the messenger RNA expression of PTH-related peptide (PTHrP) using proinflammatory cytokines, such as interleukin (IL)-1, tumor necrosis factor- without the coordination of other cytokines. In addition, PGE₂ which has been induced with IL-1, also enhanced the production of PTHrP. The IL-1-induced PTHrP production was inhibited by PG H synthetase (Cox) inhibitors, indomethacin, and also by Cox-2 inhibitor, NS398. The synovial fibroblasts expressed PGE₂ receptor subtypes, EP2, EP3, EP4, but not EP1, as detected by RT-PCR. Of the PGE₂ receptor agonists, EP4 agonist showed the most marked induction of PTHrP, and EP2 agonist partly induced the production. However, these PGE₂ receptors were not induced by the treatment with IL-1 and PGE₂.

These results suggest that induction of PGE₂ by IL-1 may be an important component of the PTHrP production of the inflammatory process in synovial tissues from patients with RA. These findings are the first to demonstrate that PGE₂ stimulates PTHrP production, which is mediated mostly by EP2 and EP4 receptors.

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