The present study investigated the influence of PGE2, E
prostanoid (EP) receptors, and their signaling pathways on matrix
metalloproteinase (MMP)-1 and IL-6 expression in synovial fibroblasts (SFs) from
rheumatoid arthritis (RA) patients. RASFs expressed all four EP receptors, with
selective induction of EP2 by TNF-α.
TNF-α time-dependently increased intracellular
cAMP/protein kinase A signaling (maximum, 6–12 h) and PGE2
secretion (maximum, 24 h). PGE2 and the EP2 agonists butaprost or
ONO-AE1-259
((16)-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydro
PGE1), in turn, induced a rapid, time-dependent (maximum,
15–30 min) increase of cAMP. Additionally, cyclooxygenase-2 inhibition
by NS-398
(N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide) reduced
the TNF-α-induced increase in IL-6 mRNA/protein, which
was restored by stimulation with PGE2 or EP2, EP3, and EP4 agonists.
In contrast, TNF-α-induced MMP-1 secretion was not
influenced by NS-398 and diminished by PGE2 via EP2. Finally,
3-isobutyl-1-methylxanthine enhanced the effects of PGE2 on MMP-1,
but not on IL-6 mRNA. In conclusion, PGE2 differentially affects
TNF-α-induced mRNA expression of proinflammatory
IL-6 and prodestructive MMP-1 regarding the usage of EP receptors and the
dependency on cAMP. Although specific blockade of EP2 receptors is considered a
promising therapeutic strategy in RA, opposite regulation of proinflammatory
IL-6 and prodestructive MMP-1 by PGE2 via EP2 may require more
complex approaches to successfully inhibit the cyclooxygenase-1/2 cAMP axis.