Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts.
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.
Díaz
Lorenza
L
Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Tlalpan 14000, México, D.F, Mexico. lorenzadiaz@gmail.com
Noyola-Martínez
Nancy
N
Barrera
David
D
Hernández
Guillermo
G
Avila
Euclides
E
Halhali
Ali
A
Larrea
Fernando
F
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001141:Aromatase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D010926:Placental Hormones / Q000276:immunology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000276:immunology*; D011375:Progesterone Reductase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors; D013250:Steroid Hydroxylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D006063:Chorionic Gonadotropin; D015850:Interleukin-6; D010926:Placental Hormones; D018167:Receptors, Calcitriol; C400545:TEI 9647; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D015096:3-Hydroxysteroid Dehydrogenases; D011375:Progesterone Reductase; D013250:Steroid Hydroxylases; D001141:Aromatase; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol