Regulation by PGE2 of the production of interleukin-6, macrophage colony stimulating factor, and vascular endothelial growth factor in human synovial fibroblasts.

1. We examined the effects of endogenous prostaglandin E(2) (PGE(2)) on the production of interleukin-6 (IL-6), macrophage colony stimulating factor (M-CSF), and vascular endothelial growth factor (VEGF) by interleukin-1beta (IL-1beta)-stimulated human synovial fibroblasts. 2. NS-398 (1 microM), a cyclo-oxygenase-2 (COX-2) inhibitor, inhibited IL-6 and VEGF production (35+/-4% and 26+/-2%, respectively) but enhanced M-CSF production (38+/-4%) by IL-1beta (1 ng ml(-1)) in synovial fibroblasts isolated from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Exogenous PGE(2) completely abolished the effects of NS-398 on the production of each mediator by OA fibroblasts stimulated with IL-1beta. 3. 8-Bromo cyclic AMP and dibutyryl cyclic AMP, cyclic AMP analogues, mimicked the effects of PGE(2) on IL-6, M-CSF, and VEGF production by OA fibroblasts. 4. The EP(2) selective receptor agonist ONO-AE1-259 (2 nM) and the EP(4) selective receptor agonist ONO-AE1-329 (2 or 20 nM), but not the EP(1) selective receptor agonist ONO-DI-004 (1 microM) and the EP(3) selective receptor agonist ONO-AE-248 (1 microM), replaced the effects of PGE(2) on IL-6, M-CSF, and VEGF production by OA and RA fibroblasts stimulated with IL-1beta in the presence of NS-398. 5. Both OA and RA fibroblasts expressed mRNA encoding EP(2) and EP(4) but not EP(1) receptors. In addition, up-regulation of EP(2) and EP(4) receptor mRNAs was observed at 3 h after IL-1beta treatment. 6. These results suggest that endogenous PGE(2) regulates the production of IL-6, M-CSF, and VEGF by IL-1beta-stimulated human synovial fibroblasts through the activation of EP(2) and EP(4) receptors with increase in cyclic AMP.