Document Detail

Effect of the interaction between lipoxygenase pathway and progesterone on the regulation of hydroxysteroid 11-Beta dehydrogenase 2 in cultured human term placental trophoblasts.
MedLine Citation:
PMID:  18032417     Owner:  NLM     Status:  MEDLINE    
Placental hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2) plays an important role in pregnancy maintenance and fetal maturation. In the event of intrauterine infection, lipoxygenase (LOX) metabolites are produced in the placenta and contribute to preterm labor and adverse fetal outcomes. On the other hand, LOX metabolites are involved in production of progesterone, which is required for pregnancy maintenance. In this study, we evaluated the interaction between the LOX pathway, progesterone, and HSD11B2. Specifically, we hypothesized that LOX metabolites would alter HSD11B2 and this effect would be mediated by progesterone. We cultured human term placental trophoblasts in the presence and absence of the LOX inhibitors Nordihydroguaiaretic acid (NDGA), AA861, and Baicalein; the LOX metabolites Leukotriene B(4) and 12(S)-Hydroxyeicosatetraenoate (12-HETE); and progesterone and progesterone receptor antagonist RU486. By radiometric conversion assay, real-time quantitative PCR, Western blot analysis, and ELISA, we examined HSD11B2 enzyme activity, HSD11B2 mRNA and HSD11B2 protein expression, and progesterone output. LOX metabolites down-regulated HSD11B2 activity and HSD11B2 expression. LOX inhibitors up-regulated HSD11B2 activity and HSD11B2 and HSD11B2 expression, and these effects were attenuated by addition of LOX metabolites. Net progesterone output was increased by LOX metabolites and decreased by LOX inhibitors. Progesterone down-regulated HSD11B2 activity and HSD11B2 and HSD11B2 expression, and these effects were blocked by RU486. Furthermore, the suppressive effect of 12-HETE on HSD11B2 activity was also reversed by RU486. We conclude that HSD11B2 in human placental trophoblasts is decreased by progesterone and increased by inhibition of endogenous LOX metabolites, and that a component of the effect of LOX metabolites on HSD11B2 is mediated by their stimulation of endogenous progesterone output.
Kazuyo Sato; Hiroshi Chisaka; Kunihiro Okamura; John R G Challis
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-11-21
Journal Detail:
Title:  Biology of reproduction     Volume:  78     ISSN:  0006-3363     ISO Abbreviation:  Biol. Reprod.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-02-27     Completed Date:  2008-05-22     Revised Date:  2010-05-07    
Medline Journal Info:
Nlm Unique ID:  0207224     Medline TA:  Biol Reprod     Country:  United States    
Other Details:
Languages:  eng     Pagination:  514-20     Citation Subset:  IM    
CIHR Group in Development and Fetal Health, Department of Physiology and Obstetrics and Gynecology and Medicine, University of Toronto, Ontario, Canada.
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MeSH Terms
11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics*,  metabolism
Benzoquinones / pharmacology
Cells, Cultured
Enzyme Activation / drug effects
Flavanones / pharmacology
Gene Expression Regulation, Enzymologic* / drug effects
Gestational Age
Lipoxygenase / metabolism,  physiology*
Lipoxygenase Inhibitors / pharmacology
Models, Biological
Nordihydroguaiaretic Acid / pharmacology
Placenta / enzymology,  metabolism
Progesterone / metabolism*,  pharmacology
RNA, Messenger / metabolism
Signal Transduction / drug effects,  physiology
Trophoblasts / drug effects,  enzymology,  metabolism*
Reg. No./Substance:
0/Benzoquinones; 0/Flavanones; 0/Lipoxygenase Inhibitors; 0/RNA, Messenger; 491-67-8/baicalein; 500-38-9/Nordihydroguaiaretic Acid; 57-83-0/Progesterone; 80809-81-0/2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; EC Dehydrogenase Type 2; EC protein, human; EC

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