Proinflammatory cytokines inhibit human placental 11β-hydroxysteroid dehydrogenase type 2 activity through Ca 2+ and cAMP pathways

Abstract

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 Ca 2+ 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 activity was attenuated using a Ca 2+ channel blocker (nifedipine), an intracellular Ca 2+ antagonist [8-( N, N-diethylamino)octyl-3,4,5-trimethoxybenzoate], or the adenylyl cyclase stimulant forskolin. Conversely, 11β-HSD2 activity was diminished in the presence of the Ca 2+ ionophore A-23187 or the adenylyl cyclase inhibitor SQ-22536. mRNA levels for 11β-HSD2 were not changed by any of the treatments. Proinflammatory cytokines inhibit human placental 11β-HSD2 activity through a mechanism that involves increased intracellular Ca 2+ and inhibition of adenylyl cyclase. This could result in excessive fetal exposure to maternal cortisol. This mechanism might mediate part of the increased risk of metabolic and cardiovascular disease in adult offspring.