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Prostaglandins and Leukotriene B₄ Are Potent Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 2 Activity in Human Choriocarcinoma JEG-3 Cells¹

^a The Lawson Research Institute, St. Joseph's Health Centre, Departments of Obstetrics and Gynaecology and Physiology, University of Western Ontario, London, Ontario, Canada N6A 4V2

The 11ß-hydroxysteroid dehydrogenase type 2 (11ß-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 11ß-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 F₂ attenuated 11ß-HSD2 activity (~40%). Paradoxically, indomethacin, an inhibitor of cyclooxygenases, inhibited (~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 11ß-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 11ß-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 11ß-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 11ß-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 11ß-HSD2 mRNA levels were not altered by the addition of LTB₄, PGE₂, or PGF₂, indicating an effect at the posttranscriptional level. In conclusion, these results demonstrate that prostaglandins and LTB₄ are potent inhibitors of 11ß-HSD2 activity in JEG-3 cells, suggesting that placental 11ß-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 11ß-HSD2.

¹ This work was supported by the Canadian MRC (Grant MT-12100 to K.Y.). D.B.H. was supported partially by an AEF Grant from Department of Obstetrics and Gynaecology, the University of Western Ontario. K.Y. is an Ontario Ministry of Health Career Scientist.

² Correspondence: K. Yang, Lawson Research Institute, 268 Grosvenor Street, London, ON, Canada N6A 4V2. FAX: 519 646 6110; kyang{at}julian.uwo.ca

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