Augmented epithelial multidrug resistance–associated protein 4 expression in peritoneal endometriosis: regulation by lipoxin A4
Multidrug resistance–associated protein 4 expression is augmented in peritoneal endometriotic lesions, where it localizes to glandular epithelial cells and is inhibited by lipoxin A4 in endometriotic epithelial cells in vitro.
Ilaria Gori, Ph.D., Yoima Rodriguez, M.Sc., Chiara Pellegrini, M.Sc., Chahin Achtari, M.D., Daniela Hornung, M.D., Ph.D., Eric Chardonnens, M.D., Dorothea Wunder, M.D., Maryse Fiche, M.D., Geraldine O. Canny, Ph.D.
Volume 99, Issue 7, Pages 1965-1973.e2, June 2013
To compare the expression of the PGE2 transporter multidrug resistanceassociated protein 4 (MRP4) in eutopic and ectopic endometrial tissue from endometriosis patients to that of control subjects and to examine whether MRP4 is regulated by the anti-inflammatory lipid Lipoxin A4 (LXA4) in endometriotic epithelial cells.
Molecular analysis in human samples and a cell line.
Two university hospitals and a private clinic.
A total of 59 endometriosis patients and 32 age- and body mass index–matched control subjects undergoing laparoscopy or hysterectomy.
Normal, eutopic, and ectopic endometrial biopsies as well as peritoneal fluid were obtained during surgery performed during the proliferative phase of the menstrual cycle. 12Z endometriotic epithelial cells were used for in vitro mechanistic studies.
Main Outcome Measure(s):
Tissue MRP4 mRNA levels was quantified by qRT-PCR and localization was analyzed using immunohistochemistry. For in vitro studies cellular MRP4 mRNA and protein were quantified by qRT-PCR and western blot, respectively. PGE2 was measured in peritoneal fluid and cell supernatants using an enzyme immunoassay (EIA).
MRP4 was expressed in eutopic and ectopic endometrium, where it was overexpressed in peritoneal lesions and localized in the cytoplasm of glandular epithelial cells. LXA4 attenuated MRP4 mRNA and protein levels in endometriotic epithelial cells in a dose-dependent manner, while not affecting the expression of enzymes involved in PGE2 metabolism. Investigations employing receptor antagonists and small interfering RNA revealed that this occurred through estrogen receptor α. Accordingly, LXA4 treatment inhibited extracellular PGE2 release.
We report for the first time that MRP4 is expressed in human endometrium, elevated in peritoneal endometriosis and modulated by LXA4 in endometriotic epithelial cells.
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