{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T21:36:26Z","timestamp":1791149786332,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2009,7,1]],"date-time":"2009-07-01T00:00:00Z","timestamp":1246406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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-\u03b1. TNF-\u03b1 time-dependently increased intracellular cAMP\/protein kinase A signaling (maximum, 6\u201312 h) and PGE2 secretion (maximum, 24 h). PGE2 and the EP2 agonists butaprost or ONO-AE1-259 ((16)-9-deoxy-9\u03b2-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydro PGE1), in turn, induced a rapid, time-dependent (maximum, 15\u201330 min) increase of cAMP. Additionally, cyclooxygenase-2 inhibition by NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide) reduced the TNF-\u03b1-induced increase in IL-6 mRNA\/protein, which was restored by stimulation with PGE2 or EP2, EP3, and EP4 agonists. In contrast, TNF-\u03b1-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-\u03b1-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.<\/jats:p>","DOI":"10.4049\/jimmunol.0900801","type":"journal-article","created":{"date-parts":[[2009,6,19]],"date-time":"2009-06-19T22:01:30Z","timestamp":1245448890000},"page":"1328-1336","source":"Crossref","is-referenced-by-count":39,"title":["Prostaglandin E2 Differentially Modulates Proinflammatory\/Prodestructive Effects of TNF-\u03b1 on Synovial Fibroblasts via Specific E Prostanoid Receptors\/cAMP"],"prefix":"10.1093","volume":"183","author":[{"given":"Elke","family":"Kunisch","sequence":"first","affiliation":[{"name":"Experimental Rheumatology Unit, Department of Orthopedics, University Hospital Jena , Jena,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Jansen","sequence":"additional","affiliation":[{"name":"Experimental Rheumatology Unit, Department of Orthopedics, University Hospital Jena , Jena,","place":["Germany"]},{"name":"Department of Internal Medicine, Division of Rheumatology, Kentucky Clinic, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiaki","family":"Kojima","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Kentucky Clinic, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivonne","family":"L\u00f6ffler","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Friedrich Schiller University Jena , Jena,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohit","family":"Kapoor","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Kentucky Clinic, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Kawai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Rubio","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Friedrich Schiller University Jena , Jena,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie J","family":"Crofford","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Kentucky Clinic, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raimund W","family":"Kinne","sequence":"additional","affiliation":[{"name":"Experimental Rheumatology Unit, Department of Orthopedics, University Hospital Jena , Jena,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,7,15]]},"reference":[{"key":"2026012811285876800_R1","first-page":"356","article-title":"Evolving concepts of rheumatoid arthritis.","volume-title":"Nature","year":"2003"},{"key":"2026012811285876800_R2","first-page":"501","article-title":"Activation of synovial fibroblasts in rheumatoid arthritis.","volume-title":"Ann. 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