title: Prostaglandin E₂ inhibits human lung fibroblast chemotaxis through disparate actions on different E-prostanoid receptors.
abstract: The migration of fibroblasts is believed to play a key role in both normal wound repair and abnormal tissue remodeling. Prostaglandin E (PGE)(2), a mediator that can inhibit many fibroblast functions including chemotaxis, was reported to be mediated by the E-prostanoid (EP) receptor EP2. PGE(2), however, can act on four receptors. This study was designed to determine if EP receptors, in addition to EP2, can modulate fibroblast chemotaxis. Using human fetal lung fibroblasts, the expression of all four EP receptors was demonstrated by Western blotting. EP2-selective and EP4-selective agonists inhibited both chemotaxis toward fibronectin in the blindwell assay and migration in a wound-closure assay. In contrast, EP1-selective and EP3-selective agonists stimulated cell migration in both assay systems. These results were confirmed using EP-selective antagonists. The role of both EP2 and EP4 receptors in mediating the PGE(2) inhibition of chemotaxis was also confirmed by small interfering RNA suppression. Furthermore, the role of EP receptors was confirmed by blocking the expected signaling pathways. Taken together, these results demonstrate that PGE(2) can act on multiple EP receptors in human lung fibroblasts, to exert disparate effects. Alterations in EP receptor expression may have the potential to alter PGE(2) action. Targeting specific EP receptors may offer therapeutic opportunities in conditions characterized by abnormal tissue repair and remodeling.
authors.affiliation: Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan.
authors.forename: Ying-Ji
authors.initials: YJ
authors.lastname: Li
authors.forename: Xing-Qi
authors.initials: XQ
authors.lastname: Wang
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sato
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kanaji
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Miok
authors.initials: M
authors.lastname: Kim
authors.forename: Joel
authors.initials: J
authors.lastname: Michalski
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Nelson
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Sun
authors.forename: Maha
authors.initials: M
authors.lastname: Farid
authors.forename: Hesham
authors.initials: H
authors.lastname: Basma
authors.forename: Amol
authors.initials: A
authors.lastname: Patil
authors.forename: Myron L
authors.initials: ML
authors.lastname: Toews
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D015153:Blotting, Western; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D034622:RNA Interference; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects
chemical_list: D005353:Fibronectins; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone