tailieunhanh - Báo cáo khoa học: Downregulation of protease-activated receptor-1 in human lung fibroblasts is specifically mediated by the prostaglandin E2 receptor EP2 through cAMP elevation and protein kinase A

Many cellular functions of lung fibroblasts are controlled by protease-acti-vated 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. | ỊFEBS Journal Downregulation of protease-activated receptor-1 in human lung fibroblasts is specifically mediated by the prostaglandin E2 receptor EP2 through cAMP elevation and protein kinase A Elena Sokolova1 Roland Hartig2 and Georg Reiser1 1 Institut fur Neurobiochemie Medizinische Fakultat Otto-von-Guericke-Universitat Magdeburg Germany 2 Institut fur Immunologie Medizinische Fakultat Otto-von-Guericke-Universitat Magdeburg Germany Keywords cAMP E prostanoid receptor lung fibroblasts prostaglandin E2 protease-activated receptor-1 Correspondence G. Reiser Institut fur Neurobiochemie Medizinische Fakultat Otto-von-Guericke-Universitaet Magdeburg Leipziger Strasse 44 D-39120 Magdeburg Germany Fax 49 391 6713097 Tel 49 391 6713088 E-mail Received 17 October 2007 revised 3 April 2008 accepted 19 May 2008 doi 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 b-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 .