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This Article Full Text Full Text (PDF) All Versions of this Article: 78/3/514    most recent biolreprod.107.064717v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sato, K. Articles by Challis, J. R.G. Search for Related Content PubMed PubMed Citation Articles by Sato, K. Articles by Challis, J. R.G. Agricola Articles by Sato, K. Articles by Challis, J. R.G.

Effect of the Interaction Between Lipoxygenase Pathway and Progesterone on the Regulation of Hydroxysteroid 11-Beta Dehydrogenase 2 in Cultured Human Term Placental Trophoblasts¹

CIHR Group in Development and Fetal Health,³ Department of Physiology and Obstetrics and Gynecology and Medicine, University of Toronto, Ontario, Canada M5S 1A8 Department of Obstetrics and Gynecology,⁴ Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan

ABSTRACT

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 B₄ 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.

HSD11B2, human placental trophoblast, hydroxysteroid 11-beta dehydrogenase 2, lipoxygenase pathway, progesterone

¹Supported by the Canadian Institute of Health Research operating grant (to J.R.G.C.).

Correspondence: ²Kazuyo Sato, Department of Physiology, University of Toronto, Room 3344, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. FAX: 416 978 4373; e-mail: kazusato{at}mail.tains.tohoku.ac.jp