1 We examined the effects of endogenous prostaglandin E[sub2] (PGE[sub2]) on the production of interleukin-6 (IL-6), macrophage colony stimulating factor (M-CSF), and vascular endothelial growth factor (VEGF) by interlcukin-1β (IL-1& beta;)-stimulated human synovial fibroblasts. 2 NS-398 (1 μM). a cyclo-oxygenase-2 (COX-2) inhibitor, inhibited IL-6 and VEGF production 135± 4% and 26±2%, respectively) but enhanced M-CSF production (3R±4%) by IL-Iβ (l ng ml[sup-1]) in synovial fibroblasts isolated from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Exogenous PGE[sub2] completely abolished the effects of NS-398 on the production of each mediator by OA fibroblasts stimulated with IL-1β 3 8-Bromo cyclic AMP and dibutyryl cyclic AMP. cyclic AMP analogues, mimicked the effects of PGE[sub2], on IL-6. M-CSF, and VEGF production by OA fibroblasts. 4 The EP[sub2] selective receptor agonist ONO-AE1-259 (2 nM) and the EP[sub4] selective receptor agonist ONO-AE1-329 (2 or 20 nM). but not the EP[sub1] selective receptor agonist ONO-DI-004 (1 μM) and the EP[sub3] selective receptor agonist ONO-AE-248 (1 μM), replaced the effects of PGE[sub2] on IL-6. M-CSF. and VEGF production by OA and RA fibroblasts stimulated with IL-1β in the presence of NS-39S. 5 Both OA and RA fibroblasts expressed mRNA encoding EP[sub2] and EP[sub4] but not EP[sub1] receptors. In addition, up-regulation of EP[sub2] and EP[sub4] receptor mRNAs was observed at 3 h after IL-1β treatment. 6 These results suggest that endogenous PGE[sub2] regulates the production of IL-6. M-CSF. and VEGF by IL-1β-stimulated human synovial fibroblasts through the activation of EP[sub2] and EP[sub4] receptors with increase in cyclic AMP. [ABSTRACT FROM AUTHOR]