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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Prostaglandin E2 Promotes Wound-Induced Migration of Intestinal Subepithelial Myofibroblasts via EP2, EP3, and EP4 Prostanoid Receptor Activation

Koichi Iwanaga, Muneyoshi Okada, Takahisa Murata, Masatoshi Hori and Hiroshi Ozaki
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 604-611; DOI: https://doi.org/10.1124/jpet.111.189845
Koichi Iwanaga
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Muneyoshi Okada
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Takahisa Murata
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Masatoshi Hori
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Hiroshi Ozaki
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Abstract

Intestinal subepithelial myofibroblasts (ISMFs) are mesenchymal cells that reside in the subepithelial region throughout the intestine. When the intestine is damaged, the migratory and mitotic responses of ISMFs are crucial for wound closure. However, their mechanism of action remains unknown. We have investigated the role of cyclooxygenase (COX) and its metabolite prostaglandin E2 (PGE2) in the wound repair process of bovine ISMFs. The action of a mechanical scratch in a layer of ISMFs in cell culture elevated the levels of both COX-2 mRNA expression and PGE2 secretion 1 and 6 h after the event. After 24 h ISMFs had migrated to and reduced the wounded area around the site of the scratch. Treatment with the COX-1/2 inhibitor indomethacin, the COX-2 inhibitor 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (CAY10404), or E prostanoid receptor 2 to 4 (EP2–EP4) antagonists significantly inhibited wound repair. Conversely, inhibition of wound closure by indomethicin was reversed by treatment with PGE2 or agonists of the receptors EP2, EP3, or EP4 but not of EP1. Although EP2 to EP4 stimulation did not influence ISMF proliferation, it did stimulate ISMF migration in the transwell cell migration assay. It is noteworthy that cell migration stimulated by EP2 and EP4 was inhibited by the tyrosine kinase receptor inhibitor genistein and also by (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid (SU6668). However, cell migration stimulated by EP3 was unaffected. Reverse transcription-polymerase chain reaction showed EP2 or EP4 stimulation elevated the level of mRNA expression for fibroblast growth factor-2, which stimulates ISMF migration. Collectively, COX-2-dependent PGE2 secretion promotes wound healing by ISMFs. PGE2-EP3 signaling may directly stimulate ISMF migration. PGE2-EP2/4 signaling indirectly stimulates ISMF migration by elevating the level of growth factor secretion.

Footnotes

  • This work was supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists and the Japan Society for the Promotion of Science.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.189845.

  • ABBREVIATIONS:

    ISMF
    intestinal subepithelial myofibroblast
    PG
    prostaglandin
    PGE2
    prostaglandin E2
    PGES
    PGE2 synthase
    cPGES
    cytosolic PGES
    mPGES
    microsomal PGES
    EP
    E prostanoid receptor
    COX
    cyclooxygenase
    FGF
    fibroblast growth factor
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    VEGF
    vascular endothelial growth factor
    HGF
    hepatocyte growth factor
    RT-PCR
    reverse transcription-polymerase chain reaction
    FBS
    fetal bovine serum
    DMEM
    Dulbecco's modified Eagle's medium
    bp
    base pairs
    CAY10404
    3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole
    SU6668
    (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid
    AH6809
    6-isopropoxy-9-oxoxanthene-2-carboxylic acid
    AH23848
    (7-[5α-([1S,1α(Z)-biphenyl]-4-ylmethoxy)-2β-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, calcium salt), hydrate
    MK886
    1-[(4-chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-α,α-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid, sodium salt
    SC-560
    5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole
    LY798106
    N-[(5-bromo-2-methoxyphenyl)sulfonyl]-3-[2-(2-naphthalenylmethyl)phenyl]-2-propenamide
    ONO-DI-004
    17S-2,5-ethano-6-oxo-17,20-dimethyl prostaglandin E1
    ONO-AE1-259-01
    11,15-O-dimethyl prostaglandin E2
    ONO-AE-248
    16S-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydro prostaglandin F2
    ONO-AE1-329
    16-(3-methoxymethyl) phenyl-ω-tetranor-3,7-dithia-prostaglandin E1.

  • Received November 8, 2011.
  • Accepted December 1, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Intestinal Myofibroblast Wound Repair by Prostaglandin E2

Koichi Iwanaga, Muneyoshi Okada, Takahisa Murata, Masatoshi Hori and Hiroshi Ozaki
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 604-611; DOI: https://doi.org/10.1124/jpet.111.189845

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Intestinal Myofibroblast Wound Repair by Prostaglandin E2

Koichi Iwanaga, Muneyoshi Okada, Takahisa Murata, Masatoshi Hori and Hiroshi Ozaki
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 604-611; DOI: https://doi.org/10.1124/jpet.111.189845
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