The
11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) is responsible for the inactivation of
glucocorticoids. This is the predominant
isozyme in the human placenta, where it is proposed to protect the fetus from high levels of maternal
cortisol. In the present study, we examined the effects of
eicosanoids on the activity of
11beta-HSD2 in human
choriocarcinoma JEG-3 cells, a well-established model for placental trophoblasts. Treatment of JEG-3 cells for 24 h with either
prostaglandin (PG) E2 or F2alpha attenuated
11beta-HSD2 activity ( approximately 40%). Paradoxically,
indomethacin, an inhibitor of
cyclooxygenases, inhibited (approximately 40%) rather than stimulated the activity of this
enzyme. This indicated that the
arachidonic acid metabolism may be diverted to other pathway(s), the products of which may inhibit
11beta-HSD2 activity. To determine whether the
lipoxygenase pathways were involved, the cells were treated with
nordihydroguaretic acid (NDGA), a blocker of all three (5-, 12-, and 15-)
lipoxygenases. NDGA caused a 3-fold increase in
11beta-HSD2 activity. To further delineate which specific
lipoxygenase pathway was involved, the cells were incubated with
zileuton, a selective inhibitor of
5-lipoxygenase. This resulted in a similar increase in
11beta-HSD2 activity, suggesting that the products of this pathway (e.g.,
leukotrienes) may be involved. Given that
leukotriene B4 (
LTB4) is the most biologically active product of the
5-lipoxygenase pathway, we treated the cells with
LTB4, which inhibited
11beta-HSD2 activity in a time- and dose-dependent manner with a maximal effect (60% reduction)
at 10 nM for 9 h. Semiquantitative reverse transcription-polymerase chain reaction analysis revealed that
11beta-HSD2 mRNA levels were not altered by the addition of
LTB4,
PGE2, or
PGF2alpha, indicating an effect at the posttranscriptional level. In conclusion, these results demonstrate that
prostaglandins and
LTB4 are potent inhibitors of
11beta-HSD2 activity in JEG-3 cells, suggesting that placental
11beta-HSD2 activity is modulated by these locally produced
eicosanoids. This is the first time that the products of
arachidonic acid metabolism have been found to regulate the activity of
11beta-HSD2.