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This Article Full Text 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 Citation Map 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. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH

Prostaglandin E₂ Differentially Modulates Proinflammatory/Prodestructive Effects of TNF- on Synovial Fibroblasts via Specific E Prostanoid Receptors/cAMP¹

Elke Kunisch^2,*, Anne Jansen^*,, Fumiaki Kojima, Ivonne Löffler^3,, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The study was supported by the German Federal Ministry of Education and Research (BMBF; Grants FKZ 01ZZ9602, 01ZZ0105, and 010405 to R.W.K., Interdisciplinary Center for Clinical Research (IZKF) Jena, including a grant for junior researchers to E.K.; Grants FKZ 0312704B and 0313652B to R.W.K., Jena Center for Bioinformatics; Grant 01GS0413, NGFN-2 to R.W.K.), the German Research Foundation (DFG; Grants KI 439/7-1 and KI 439/6-1 to R.W.K.), National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant 1 R01 AR049010 to L.J.C., and a grant for the advancement of female scientists to Elke Kunisch (LUBOM Thuringia). Anne Jansen was supported by a stipend from the Friends of the Friedrich Schiller University Jena, as well as by travel allowances from Jenapharm and the Boehringer Ingelheim Foundation.

² 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

³ Current address: Department of Internal Medicine III, University Hospital Jena, Jena, Germany.

⁴ Abbreviations used in this paper: RA, rheumatoid arthritis; RASF, rheumatoid arthritis synovial fibroblast; MMP, matrix metalloproteinase; COX, cyclooxygenase; EP, E prostanoid; NS-398, N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide; IBMX, 3-isobutyl-1-methylxanthine; PKA, protein kinase A.

⁵ The online version of this article contains supplemental material.