title: Differential regulation of airway smooth muscle cell migration by E-prostanoid receptor subtypes.
abstract: Migration of airway smooth muscle (ASM) cells plays an important role in the pathophysiology of airway hyperresponsiveness and remodeling in asthma. It has been reported that prostaglandin (PG)E2 inhibits migration of ASM cells. Although PGE2 regulates cellular functions via binding to distinct prostanoid EP receptors, the role of EP receptor subtypes in mechanisms underlying cell migration has not been fully elucidated. We investigated the role of EP receptors in the inhibitory effects of PGE2 on the migration of human ASM cells. Migration induced by platelet-derived growth factor (PDGF)-BB (10 ng/ml, 6 h) was assessed by a chemotaxis chamber assay. PDGF-BB-induced cell migration was inhibited by PGE2, the specific EP2 agonist ONO-AE1-259-01, the specific EP4 agonist ONO-AE1-329, and cAMP-mobilizing agents. The inhibition of cell migration by PGE2 was significantly reversed by a blockade of EP2 and EP4 receptors using antagonists or transfection with siRNAs. Moreover, PGE2, the EP2 agonist, and the EP4 agonist significantly increased phosphorylation of small heat shock protein 20, one of the protein substrates for protein kinase A (PKA), with depolymerization of actin. In contrast, the EP3 agonist ONO-AE-248 significantly promoted baseline cell migration without affecting PDGF-BB-induced cell migration. In summary, activation of EP2 and EP4 receptors and subsequent activation of the cAMP/PKA pathway are the main mechanisms of inhibition of ASM cell migration by PGE2. HSP20 phosphorylation by PKA is possibly involved in this mechanism. Conversely, EP3 is potent in promoting cell migration. EP receptor subtypes may be novel therapeutic target molecules in airway remodeling and asthma.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Aso
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.forename: Akemi
authors.initials: A
authors.lastname: Mori
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Suganuma
authors.forename: Masataka
authors.initials: M
authors.lastname: Morioka
authors.forename: Norihiro
authors.initials: N
authors.lastname: Takahara
authors.forename: Masashi
authors.initials: M
authors.lastname: Kondo
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism*; D022502:Stress Fibers / Q000187:drug effects
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D050886:HSP20 Heat-Shock Proteins; C494382:HSPB6 protein, human; D010982:Platelet-Derived Growth Factor; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone