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- Title
Downregulation of protease-activated receptor-1 in human lung fibroblasts is specifically mediated by the prostaglandin E<sub>2</sub> receptor EP2 through cAMP elevation and protein kinase A.
- Authors
Sokolova, Elena; Hartig, Roland; Reiser, Georg
- Abstract
Many cellular functions of lung fibroblasts are controlled by protease-activated receptors (PARs). In fibrotic diseases, PAR-1 plays a major role in controlling fibroproliferative and inflammatory responses. Therefore, in these diseases, regulation of PAR-1 expression plays an important role. Using the selective prostaglandin EP2 receptor agonist butaprost and cAMP-elevating agents, we show here that prostaglandin (PG)E2, via the prostanoid receptor EP2 and subsequent cAMP elevation, downregulates mRNA and protein levels of PAR-1 in human lung fibroblasts. Under these conditions, the functional response of PAR-1 in fibroblasts is reduced. These effects are specific for PGE2. Activation of other receptors coupled to cAMP elevation, such as β-adrenergic and adenosine receptors, does not reproduce the effects of PGE2. PGE2-mediated downregulation of PAR-1 depends mainly on protein kinase A activity, but does not depend on another cAMP effector, the exchange protein activated by cAMP. PGE2-induced reduction of PAR-1 level is not due to a decrease of PAR-1 mRNA stability, but rather to transcriptional regulation. The present results provide further insights into the therapeutic potential of PGE2 to specifically control fibroblast function in fibrotic diseases.
- Subjects
PROSTANOIDS; FIBROBLASTS; LUNGS; PROSTAGLANDINS; PROTEIN kinases
- Publication
FEBS Journal, 2008, Vol 275, Issue 14, p3669
- ISSN
1742-464X
- Publication type
Article
- DOI
10.1111/j.1742-4658.2008.06511.x