Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor-mediated cervical cell-specific mechanisms.
BACKGROUND
Prostaglandins play important roles in parturition and have been used to induce cervical ripening and labor. Prior to cervical ripening at term, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is highly expressed in the cervix and metabolizes cyclooxygenase-2-mediated increases in active prostaglandin E2 (PGE2) to inactive 15-keto PGE2. At term, 15-PGDH gene expression decreases and PGE2 accumulates, leading to cervical ripening and labor. Previously, we found that the cervical isoform of microphthalmia-associated transcription factor (MiTF-CX) serves as a progestational transcription factor that represses IL-8 and hypoxia-mediated increases in cyclooxygenase-2.


OBJECTIVE
We tested the hypothesis that PGE2 regulates its own inactivation through MiTF-CX.


METHODS
We used human cervical stromal cells to investigate the regulation of 15-PGDH.


METHODS
This was a laboratory-based study using cells from clinical tissue samples.


METHODS
We evaluated the mechanisms by which PGE2 regulates 15-PGDH in human cervical stromal cells.


RESULTS
PGE2 repressed MiTF-CX and 15-PGDH, whereas ectopic overexpression of MiTF-CX induced 15-PGDH expression levels. Stabilization of HIF-1α by deferoxamine resulted in concomitant down-regulation of MiTF-CX and 15-PGDH. Ectopic overexpression of MiTF-CX abrogated PGE2- and deferoxamine-mediated loss of MiTF-CX and 15-PGDH. PGE2-induced loss of MiTF-CX and 15-PGDH was mediated through prostaglandin E2 receptor (EP2) receptors (PTGER2), but not cAMP.


CONCLUSIONS
The 15-PGDH gene is a MiTF-CX target gene in cervical stromal cells and is down-regulated by PGE2 through EP2 receptors. The findings suggest that EP2 receptor-specific antagonists may be used as an adjunct to present clinical management for the prevention of preterm cervical ripening and preterm labor.
The Cecil H. and Ida Green Center for Reproductive Biology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032.
A Hari
AH
Kishore
David
D
Owens
R Ann
RA
Word
D002478:Cells, Cultured; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D051739:Microphthalmia-Associated Transcription Factor; C545644:PTGER2 protein, human; D020033:Protein Isoforms; D058307:Receptors, Prostaglandin E, EP2 Subtype; C026346:15-ketoprostaglandin E2; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone