1 We examined the e ects 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-1b (IL-1b)-stimulated human synovial ®broblasts. 2 NS-398 (1 mM), 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-1b (1 ng ml 71 ) in synovial ®broblasts isolated from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Exogenous PGE 2 completely abolished the e ects of NS-398 on the production of each mediator by OA ®broblasts stimulated with IL-1b. 3 8-Bromo cyclic AMP and dibutyryl cyclic AMP, cyclic AMP analogues, mimicked the e ects of PGE 2 on IL-6, M-CSF, and VEGF production by OA ®broblasts. 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 mM) and the EP 3 selective receptor agonist ONO-AE-248 (1 mM), replaced the e ects of PGE 2 on IL-6, M-CSF, and VEGF production by OA and RA ®broblasts stimulated with IL-1b in the presence of NS-398. 5 Both OA and RA ®broblasts 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-1b treatment. 6 These results suggest that endogenous PGE 2 regulates the production of IL-6, M-CSF, and VEGF by IL-1b-stimulated human synovial ®broblasts through the activation of EP 2 and EP 4 receptors with increase in cyclic AMP.

The present results indicate that the activation of NF-kappaB plays an important role in the proliferative response to IL-1beta in human fibroblasts, and suggest that PGE2 acts as a modulator of cell proliferation in inflamed synovial tissue. It appears that the ability to produce soluble factors in RA synovial fibroblasts is not intrinsic. However, the response to IL-1beta in RA cells seems to be greater than that in OA cells.