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

We examined the effects of endogenous prostaglandin E2 (PGE2) on the production of interleukin-6 (IL-6), macrophage colony stimulating factor (M-CSF), and vascular endothelial growth factor (VEGF) by interleukin-1β (IL-1β)-stimulated human synovial fibroblasts. NS-398 (1 μM), 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-1β (1 ng ml−1) in synovial fibroblasts isolated from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Exogenous PGE2 completely abolished the effects of NS-398 on the production of each mediator by OA fibroblasts stimulated with IL-1β. 8-Bromo cyclic AMP and dibutyryl cyclic AMP, cyclic AMP analogues, mimicked the effects of PGE2 on IL-6, M-CSF, and VEGF production by OA fibroblasts. The EP2 selective receptor agonist ONO-AE1-259 (2 nM) and the EP4 selective receptor agonist ONO-AE1-329 (2 or 20 nM), but not the EP1 selective receptor agonist ONO-DI-004 (1 μM) and the EP3 selective receptor agonist ONO-AE-248 (1 μM), replaced the effects of PGE2 on IL-6, M-CSF, and VEGF production by OA and RA fibroblasts stimulated with IL-1β in the presence of NS-398. Both OA and RA fibroblasts expressed mRNA encoding EP2 and EP4 but not EP1 receptors. In addition, up-regulation of EP2 and EP4 receptor mRNAs was observed at 3 h after IL-1β treatment. These results suggest that endogenous PGE2 regulates the production of IL-6, M-CSF, and VEGF by IL-1β-stimulated human synovial fibroblasts through the activation of EP2 and EP4 receptors with increase in cyclic AMP. British Journal of Pharmacology (2002) 136, 287–295; doi:10.1038/sj.bjp.0704705