Prostaglandin E2 differentially modulates proinflammatory/prodestructive effects of TNF-alpha on synovial fibroblasts via specific E prostanoid receptors/cAMP.
The present study investigated the influence of PGE(2), 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-alpha. TNF-alpha time-dependently increased intracellular cAMP/protein kinase A signaling (maximum, 6-12 h) and PGE(2) secretion (maximum, 24 h). PGE(2) and the EP2 agonists butaprost or ONO-AE1-259 ((16)-9-deoxy-9beta-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydro PGE(1)), 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-alpha-induced increase in IL-6 mRNA/protein, which was restored by stimulation with PGE(2) or EP2, EP3, and EP4 agonists. In contrast, TNF-alpha-induced MMP-1 secretion was not influenced by NS-398 and diminished by PGE(2) via EP2. Finally, 3-isobutyl-1-methylxanthine enhanced the effects of PGE(2) on MMP-1, but not on IL-6 mRNA. In conclusion, PGE(2) differentially affects TNF-alpha-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 PGE(2) via EP2 may require more complex approaches to successfully inhibit the cyclooxygenase-1/2 cAMP axis.
Kunisch
Elke
E
Experimental Rheumatology Unit, Department of Orthopedics, University Hospital Jena, Jena, Germany. elke.kunisch@med.uni-jena.de
Jansen
Anne
A
Kojima
Fumiaki
F
Löffler
Ivonne
I
Kapoor
Mohit
M
Kawai
Shinichi
S
Rubio
Ignacio
I
Crofford
Leslie J
LJ
Kinne
Raimund W
RW
D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000819:agonists / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D011451:Prostaglandin-Endoperoxide Synthases; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D013583:Synovial Membrane / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015850:Interleukin-6; D018078:Receptors, Prostaglandin E; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone