Induction of PGF2α synthesis by cortisol through GR dependent induction of CBR1 in human amnion fibroblasts

Endocrinology. 2014 Aug;155(8):3017-24. doi: 10.1210/en.2013-1848. Epub 2014 Mar 21.

Abstract

Abundant evidence indicates a pivotal role of prostaglandin F2α (PGF2α) in human parturition. Both the fetal and maternal sides of the fetal membranes synthesize PGF2α. In addition to the synthesis of PGF2α from PGH2 by PGF synthase (PGFS), PGF2α can also be converted from PGE2 by carbonyl reductase 1 (CBR1). Here, we showed that there was concurrent increased production of cortisol and PGF2α in association with the elevation of CBR1 in human amnion obtained at term with labor versus term without labor. In cultured primary human amnion fibroblasts, cortisol (0.01-1μM) increased PGF2α production in a concentration-dependent manner, in parallel with elevation of CBR1 levels. Either siRNA-mediated knockdown of glucocorticoid receptor (GR) expression or GR antagonist RU486 attenuated the induction of CBR1 by cortisol. Chromatin immunoprecipitation (ChIP) showed an increased enrichment of both GR and RNA polymerase II to CBR1 promoter. Knockdown of CBR1 expression with siRNA or inhibition of CBR1 activity with rutin decreased both basal and cortisol-stimulated PGF2α production in human amnion fibroblasts. In conclusion, CBR1 may play a critical role in PGF2α synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF2α via GR-mediated induction of CBR1 in human amnion fibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF2α in human amnion tissue with labor, and these findings may account for the increased production of PGF2α in the fetal membranes prior to the onset of labor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / metabolism
  • Alcohol Oxidoreductases / metabolism*
  • Aldehyde Reductase / metabolism
  • Aldo-Keto Reductase Family 1 Member C3
  • Amnion / cytology
  • Amnion / metabolism*
  • Cells, Cultured
  • Cyclooxygenase 2 / metabolism
  • Dinoprost / biosynthesis*
  • Female
  • Fibroblasts / metabolism*
  • Group IV Phospholipases A2 / metabolism
  • Humans
  • Hydrocortisone / physiology*
  • Hydroxyprostaglandin Dehydrogenases / metabolism
  • Immunohistochemistry
  • Labor, Obstetric / metabolism
  • Pregnancy
  • Receptors, Glucocorticoid / metabolism

Substances

  • Receptors, Glucocorticoid
  • Dinoprost
  • 3-Hydroxysteroid Dehydrogenases
  • Alcohol Oxidoreductases
  • Hydroxyprostaglandin Dehydrogenases
  • CBR1 protein, human
  • AKR1B1 protein, human
  • Aldehyde Reductase
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Group IV Phospholipases A2
  • Hydrocortisone