Submitted August 5, 2007
Returned for revision August 31, 2007
Accepted November 8, 2007
Mechanisms of Hormone Action
Effect of the Interaction Between Lipoxygenase Pathway and Progesterone on the Regulation of Hydroxysteroid 11-Beta Dehydrogenase 2 in Cultured Human Term Placental Trophoblasts
Kazuyo Sato *,
Hiroshi Chisaka ,
Kunihiro Okamura ,
and
John R. G. Challis
* To whom correspondence should be addressed. E-mail: kazusato{at}mail.tains.tohoku.ac.jp.
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 LOX pathway and progesterone on 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/absence of LOX inhibitors, Nordihydroguaiaretic acid (NDGA), AA861 and Baicalein; LOX metabolites, Leukotriene B4 and 12(S)-Hydroxyeicosatetraenoate; progesterone and progesterone receptor antagonist RU486. By radiometric conversion assay, real-time quantitative RT-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, 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, 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.
Key words:
Human placental trophoblast •
Hydroxysteroid 11-beta dehydrogenase 2 •
Progesterone •
lipoxygenase pathway
