Regulation by PGE 2 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 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‐1β (IL‐1β)‐stimulated human synovial fibroblasts. NS‐398 (1 μ M ), a cyclo‐oxygenase‐...

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Published in:British journal of pharmacology 2009-02, Vol.136 (2), p.287-295
Main Authors: Inoue, Hideo, Takamori, Makiko, Shimoyama, Yoshihito, Ishibashi, Hideaki, Yamamoto, Seizo, Koshihara, Yasuko
Format: Article
Language:English
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Summary: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‐1β (IL‐1β)‐stimulated human synovial fibroblasts. NS‐398 (1 μ M ), 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 PGE 2 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 PGE 2 on IL‐6, M‐CSF, and VEGF production by OA fibroblasts. The EP 2 selective receptor agonist ONO‐AE1‐259 (2 n M ) and the EP 4 selective receptor agonist ONO‐AE1‐329 (2 or 20 n M ), but not the EP 1 selective receptor agonist ONO‐DI‐004 (1 μ M ) and the EP 3 selective receptor agonist ONO‐AE‐248 (1 μ M ), replaced the effects of PGE 2 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 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‐1β treatment. These results suggest that endogenous PGE 2 regulates the production of IL‐6, M‐CSF, and VEGF by IL‐1β‐stimulated human synovial fibroblasts through the activation of EP 2 and EP 4 receptors with increase in cyclic AMP. British Journal of Pharmacology (2002) 136 , 287–295; doi: 10.1038/sj.bjp.0704705
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0704705