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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900801v1 183/2/1328    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kunisch, E. Articles by Kinne, R. W. PubMed PubMed Citation Articles by Kunisch, E. Articles by Kinne, R. W.

Prostaglandin E₂ Differentially Modulates Proinflammatory/Prodestructive Effects of TNF- on Synovial Fibroblasts via Specific E Prostanoid Receptors/cAMP

Elke Kunisch^*, Anne Jansen^*,, Fumiaki Kojima, Ivonne Löffler, Mohit Kapoor, Shinichi Kawai, Ignacio Rubio, Leslie J. Crofford and Raimund W. Kinne^*

^*Experimental Rheumatology Unit, Department of Orthopedics, University Hospital Jena, Jena, Germany; Department of Internal Medicine, Division of Rheumatology, Kentucky Clinic, University of Kentucky, Lexington, KY 40536; Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena, Germany; and Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Tokyo, Japan

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-. TNF- 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--induced increase in IL-6 mRNA/protein, which was restored by stimulation with PGE₂ or EP2, EP3, and EP4 agonists. In contrast, TNF--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--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.

Address correspondence and reprint requests to Dr. Elke Kunisch, Experimental Rheumatology Unit, Department of Orthopedics, University Hospital Jena, Klosterlausnitzer Strasse 81, D-07607 Eisenberg, Germany. E-mail address: elke.kunisch{at}med.uni-jena.de