Proinflammatory cytokines inhibit human placental 11beta-hydroxysteroid dehydrogenase type 2 activity through Ca2+ and cAMP pathways.

Excessive fetal exposure to glucocorticoids has been implicated in the etiology of adult metabolic and cardiovascular disease. Placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) may protect the fetus from excessive glucocorticoid exposure. Maternal stress may be accompanied by elevated levels of cortisol and increased proinflammatory cytokines [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α)]. We hypothesize that proinflammatory cytokines inhibit human placental 11β-HSD activity. We incubated explant cultures of term human placental villi in the presence or absence of 10 ng/ml IL-1β, IL-6, or TNF-α, with or without agonists or antagonists of intracellular Ca2+ and adenylyl cyclase. Activity for 11β-HSD2 was estimated using a radioisotope assay, and mRNA was measured using quantitative RT-PCR. All cytokines significantly (P ≤ 0.05) reduced 11β-HSD2 activity (>75% suppression); maximal inhibition occurred within 2 h and was maintained for at least 24 h. The IL-1β-induced inhibitory ...