title: Prostaglandin E2 switches from a stimulator to an inhibitor of cell migration after epithelial-to-mesenchymal transition.
abstract: Epithelial-mesenchymal transition (EMT) is critical for embryonic development, and this process is recapitulated in adults during wound healing, tissue regeneration, fibrosis and cancer progression. Cell migration is believed to play a key role in both normal wound repair and in abnormal tissue remodeling. Prostaglandin E2 (PGE2) inhibits fibroblast chemotaxis, but stimulates chemotaxis in airway epithelial cells. The current study was designed to explore the role of PGE2 and its four receptors on airway epithelial cell migration following EMT using both the Boyden blindwell chamber chemotaxis assay and the wound closure assay. EMT in human bronchial epithelial cells (HBECs) was induced by TGF-β1 and a mixture of cytokines (IL-1β, TNF-α, and IFN-γ). PGE2 and selective agonists for all four EP receptors stimulated chemotaxis and wound closure in HBECs. Following EMT, the EP1 and EP3 agonists were without effect, while the EP2 and EP4 agonists inhibited chemotaxis as did PGE2. The effects of the EP2 and EP4 receptors on HBEC and EMT cell migration were further confirmed by blocking the expected signaling pathways. Taken together, these results demonstrate that PGE2 switches from a stimulator to an inhibitor of cell migration following EMT of airway epithelial cells and that this inhibition is mediated by an altered effect of EP2 and EP4 signaling and an apparent loss of the stimulatory effects of EP1 and EP3. Change in the PGE2 modulation of chemotaxis may play a role in repair following injury.
authors.affiliation: Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan.
authors.forename: Ying-Ji
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kanaji
authors.affiliation: Department of Respiratory Disease, Affiliated Hospital of Hebei United University, Hebei, China.
authors.forename: Xing-Qi
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakanishi
authors.affiliation: Internal Medicine, Jeju Medical College, Jeju-si, Republic of Korea.
authors.forename: Miok
authors.initials: M
authors.lastname: Kim
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Michalski
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Nelson
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Maha
authors.initials: M
authors.lastname: Farid
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Hesham
authors.initials: H
authors.lastname: Basma
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Amol
authors.initials: A
authors.lastname: Patil
authors.affiliation: Pharmacology, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Myron L
authors.initials: ML
authors.lastname: Toews
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, United States. Electronic address: srennard@unmc.edu.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*
chemical_list: D016207:Cytokines; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone
keywords: Chemotaxis, Tissue repair; Epithelial–mesenchymal transition; PGE(2)