Abstract
Elevated placental proinflammatory cytokine release is associated with miscarriage, preterm labor and preeclampsia. Specifically, tumor necrosis factor-alpha (TNF-alpha)-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-alpha. The effects of calcitriol on synthesis of mRNAs encoding interleukin-6 (IL-6), interferon-gamma (IFN-gamma), and TNF-alpha were measured by real time RT-PCR. Secreted cytokines were quantified by ELISA. The effects of TNF-alpha on CYP24A1, chorionic gonadotropin (hCG), 3beta-hydroxysteroid dehydrogenase (HSD3B1) and P(450)-aromatase (CYP19) mRNA expression were also studied. TNF-alpha stimulated IL-6, IFN-gamma 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-alpha also significantly inhibited expression of hCG, HSD3B1 and CYP19 genes, and stimulated CYP24A1 gene expression. These data show that calcitriol prevents TNF-alpha induction of inflammatory cytokines through a process likely to be mediated by the vitamin D receptor. We conclude that TNF-alpha inhibits placental hormone synthesis and stimulates calcitriol catabolism by regulating enzymes involved in these processes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors
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3-Hydroxysteroid Dehydrogenases / metabolism
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Aromatase / genetics
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Aromatase / immunology
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Aromatase / metabolism
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Calcitriol / analogs & derivatives
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Calcitriol / immunology*
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Calcitriol / metabolism
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Calcitriol / pharmacology
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Cells, Cultured
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Chorionic Gonadotropin / genetics
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Chorionic Gonadotropin / immunology
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Chorionic Gonadotropin / metabolism
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Dose-Response Relationship, Immunologic
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Female
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / immunology
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Humans
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Immune Tolerance / drug effects
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Placental Hormones / immunology*
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Pregnancy
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Pregnancy Complications / immunology*
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Progesterone Reductase / genetics
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Progesterone Reductase / immunology
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Progesterone Reductase / metabolism
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Receptors, Calcitriol / antagonists & inhibitors
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Steroid Hydroxylases / genetics
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Steroid Hydroxylases / immunology
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Steroid Hydroxylases / metabolism
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Trophoblasts / drug effects
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Trophoblasts / immunology*
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Trophoblasts / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism*
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Vitamin D3 24-Hydroxylase
Substances
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Chorionic Gonadotropin
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Interleukin-6
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Placental Hormones
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Receptors, Calcitriol
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TEI 9647
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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3-Hydroxysteroid Dehydrogenases
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Progesterone Reductase
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Steroid Hydroxylases
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Aromatase
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CYP24A1 protein, human
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Vitamin D3 24-Hydroxylase
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Calcitriol