Prostaglandin E2is an enhancer of interleukin-1β-induced expression of membrane-associated prostaglandin E synthase in rheumatoid synovial fibroblasts
| Autor: | Hiroaki Naraba, Haruhito Aoki, Moroe Beppu, Shinichi Kawai, Fumiaki Kojima, Yasuharu Sasaki |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
Forskolin biology medicine.medical_treatment Prostaglandin E2 receptor Immunology EP4 Receptor Prostaglandin E synthase Molecular biology chemistry.chemical_compound medicine.anatomical_structure Endocrinology Rheumatology chemistry Internal medicine medicine biology.protein Immunology and Allergy lipids (amino acids peptides and proteins) Pharmacology (medical) Cyclooxygenase Synovial membrane Prostaglandin E2 Prostaglandin E medicine.drug |
| Zdroj: | Arthritis & Rheumatism. 48:2819-2828 |
| ISSN: | 0004-3591 |
| DOI: | 10.1002/art.11261 |
| Popis: | Objective Membrane-associated prostaglandin E synthase (mPGES) is a recently identified terminal enzyme of the arachidonic acid cascade, which converts PGH2 to PGE2 in rheumatoid arthritis synovial fibroblasts (RASFs). This study was undertaken to investigate factors regulating the expression of mPGES. Methods RASFs were treated with interleukin-1β (IL-1β), indomethacin, NS-398, rofecoxib, or meloxicam. The effects of PGE2 and selective agonists for PGE2 receptor subtypes (EP1, EP2, EP3, and EP4) were also studied. Expression of mPGES messenger RNA (mRNA) and protein was measured by Northern and Western blot analysis, respectively. EP receptor mRNA expression in RASFs was determined by reverse transcriptase–polymerase chain reaction. Production of PGE2 and cAMP was measured by enzyme-linked immunosorbent assay. Results The enhanced expression of mPGES mRNA and protein in IL-1β–stimulated RASFs was attenuated by the addition of indomethacin, NS-398, rofecoxib, or meloxicam. This reduction of expression was reversed by PGE2. IL-1β–induced PGES activity, measured by conversion of PGH2 to PGE2, was decreased by rofecoxib. EP2 and EP4 receptor mRNA was detected in RASFs. EP2 and EP4 agonists, as well as PGE2, restored the inhibitory effect of rofecoxib on mPGES expression. The effect of PGE2 was mimicked by forskolin, a direct activator of adenylate cyclase. Intracellular cAMP was increased by IL-1β and was inhibited by rofecoxib. Conclusion Enhancement of mPGES expression by PGE2 via the EP2/EP4 receptors with an increase in cAMP may play an important role in articular inflammation in patients with RA. It also seems that cyclooxygenase 2 (COX-2) inhibitors decrease PGE2 production not only by direct inhibition of COX-2, but also by reducing mPGES expression in activated RASFs. |
| Databáze: | OpenAIRE |
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