title: Vitamin D and the regulation of placental inflammation.
abstract: The vitamin D-activating enzyme 1α-hydroxylase (CYP27B1) and vitamin D receptor (VDR) support anti-inflammatory responses to vitamin D in many tissues. Given the high basal expression of CYP27B1 and VDR in trophoblastic cells from the placenta, we hypothesized that anti-inflammatory effects of vitamin D may be particularly important in this organ. Pregnant wild type (WT) mice i.p. injected with LPS showed elevated expression of mouse Cyp27b1 (4-fold) and VDR (6-fold). Similar results were also obtained after ex vivo treatment of WT placentas with LPS. To assess the functional impact of this, we carried out ex vivo studies using placentas -/- for fetal (trophoblastic) Cyp27b1 or VDR. Vehicle-treated -/- placentas showed increased expression of IFN-γ and decreased expression of IL-10 relative to +/+ placentas. LPS-treated -/- placentas showed increased expression of TLR2, IFN-γ, and IL-6. Array analyses identified other inflammatory factors that are dysregulated in Cyp27b1(-/-) versus Cyp27b1(+/+) placentas after LPS challenge. Data highlighted enhanced expression of IL-4, IL-15, and IL-18, as well as several chemokines and their receptors, in Cyp27b1(-/-) placentas. Similar results for IL-6 expression were observed with placentas -/- for trophoblastic VDR. Finally, ex vivo treatment of WT placentas with the substrate for Cyp27b1, 25-hydroxyvitamin D(3), suppressed LPS-induced expression of IL-6 and the chemokine Ccl11. These data indicate that fetal (trophoblastic) vitamin D plays a pivotal role in controlling placental inflammation. In humans, this may be a key factor in placental responses to infection and associated adverse outcomes of pregnancy.
authors.affiliation: Orthopaedic Hospital Research Center, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Nancy Q
authors.initials: NQ
authors.lastname: Liu
authors.forename: Amber T
authors.initials: AT
authors.lastname: Kaplan
authors.forename: Venu
authors.initials: V
authors.lastname: Lagishetty
authors.forename: Yuxin B
authors.initials: YB
authors.lastname: Ouyang
authors.forename: Yi
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Charles F
authors.initials: CF
authors.lastname: Simmons
authors.forename: Ozlem
authors.initials: O
authors.lastname: Equils
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D000818:Animals; D002112:Calcifediol / Q000494:pharmacology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D019409:Interleukin-15 / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010920:Placenta / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010922:Placenta Diseases / Q000276:immunology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D018167:Receptors, Calcitriol / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics; D014327:Trophoblasts / Q000166:cytology / Q000276:immunology; D014807:Vitamin D
chemical_list: D018925:Chemokines; D019409:Interleukin-15; D020382:Interleukin-18; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018167:Receptors, Calcitriol; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D014807:Vitamin D; D015847:Interleukin-4; D007371:Interferon-gamma; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002112:Calcifediol