title: Regulation by PGE2 of the production of interleukin-6, macrophage colony stimulating factor, and vascular endothelial growth factor in human synovial fibroblasts.
abstract: 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.
authors: Research Laboratory, Minophagen Pharmaceutical Co., 2-2-3 Komatsubara, Zama-shi, Kanagawa 228-0002, Japan. inoue@lab.minophagen.co.jp
authors: Hideo
authors: H
authors: Inoue
authors: Makiko
authors: M
authors: Takamori
authors: Yoshihito
authors: Y
authors: Shimoyama
authors: Hideaki
authors: H
authors: Ishibashi
authors: Seizo
authors: S
authors: Yamamoto
authors: Yasuko
authors: Y
authors: Koshihara
mesh_terms: D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D008222:Lymphokines / Q000096:biosynthesis*; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D007375:Interleukin-1; D015850:Interleukin-6; D008222:Lymphokines; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016173:Macrophage Colony-Stimulating Factor; D015232:Dinoprostone