Involvement of prostaglandin E-2 in interleukin-1 alpha-induced parathyroid hormone-related peptide production in synovial fibroblasts of patients with rheumatoid arthritis

Synovial fibroblasts, established in culture from patients with RA, were tr eated with proinflammatory cytokines and prostaglandin E-2 (PGE(2)) for 24 h; These cells enhanced the production and the messenger RNA expression of PTH-related peptide (PTHrP) using proinflammatory cytokines, such as interl eukin (IL)-1 alpha, tumor necrosis factor-alpha without the coordination of other cytokines. In addition, PGE(2) which has been induced with IL-1, als o enhanced the production of PTHrP. The IL-1 alpha -induced PTRrP productio n was inhibited by PG H synthetase (Cox) inhibitors, indomethacin, and also by Cox-a inhibitor, NS398. The synovial fibroblasts expressed PGE(2) recep tor subtypes, EP2, EP3, EP4, but not EP1, as detected by RT-PCR, Of the PGE , receptor agonists, EP4 agonist showed the most marked induction of PTHrP, and EP2 agonist partly induced the production. However, these PGE(2) recep tors were not induced by the treatment with IL-1 alpha and PGE(2). These results suggest that induction of PGE, by IL-1 alpha may be an import ant component of the PTHrP production of the inflammatory process in synovi al tissues from patients with RA. These findings are the first to demonstra te that PGE(2) stimulates PTHrP production, which is mediated mostly by EP2 and EP4 receptors.