Differential regulation of airway smooth muscle cell migration by e-prostanoid receptor subtypes

Hiromichi Aso, Satoru Ito, Akemi Mori, Nobukazu Suganuma, Masataka Morioka, Norihiro Takahara, Masashi Kondo, Yoshinori Hasegawa

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 ofhuman 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 kinaseA(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 ASMcellmigration by PGE2. HSP20 phosphorylation by PKAis possibly involved in thismechanism.Conversely, EP3 is potent in promoting cell migration. EP receptor subtypes may be novel therapeutic targetmolecules in airway remodeling and asthma.

Original languageEnglish
Pages (from-to)322-329
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume48
Issue number3
DOIs
Publication statusPublished - 01-03-2013

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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