Calcitriol inhibits TNF-α-induced inflammatory cytokines in human trophoblasts

Elevated placental proinflammatory cytokine release is associated with miscarriage, preterm labor and preeclampsia. Specifically, tumor necrosis factor-α (TNF-α)-induced cytokines may threaten pregnancy outcome. Since trophoblasts produce calcitriol, a hormone with strong immunosuppressive properties, we assessed the effects of this secosteroid on inflammatory cytokines induced in trophoblasts by challenge with TNF-α. The effects of calcitriol on synthesis of mRNAs encoding interleukin-6 (IL-6), interferon-γ (IFN-γ), and TNF-α were measured by real time RT-PCR. Secreted cytokines were quantified by ELISA. The effects of TNF-α on CYP24A1, chorionic gonadotropin (hCG), 3β-hydroxysteroid dehydrogenase (HSD3B1) and P450-aromatase (CYP19) mRNA expression were also studied. TNF-α stimulated IL-6, IFN-γ and its own expression more than 3-fold over controls (P < 0.05). Calcitriol inhibited the expression profile of inflammatory cytokine genes in a dose–response manner (P < 0.05). This effect was prevented by addition of the vitamin D receptor antagonist TEI-9647. TNF-α also significantly inhibited expression of hCG, HSD3B1 and CYP19 genes, and stimulated CYP24A1 gene expression. These data show that calcitriol prevents TNF-α induction of inflammatory cytokines through a process likely to be mediated by the vitamin D receptor. We conclude that TNF-α inhibits placental hormone synthesis and stimulates calcitriol catabolism by regulating enzymes involved in these processes.