title: Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway.
abstract: The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D), is a potent inducer of the antimicrobial protein cathelicidin, CAMP (LL37). In macrophages this response is dependent on intracrine synthesis of 1,25(OH)(2)D from precursor 25-hydroxyvitamin D (25OHD), catalyzed by the enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1). In view of the fact that trophoblastic cells also express abundant CYP27B1, we postulated a similar intracrine pathway for induction of CAMP in the placenta. Analysis of placenta explants, primary cultures of human trophoblast, and the 3A trophoblastic cell line treated with 1,25(OH)(2)D (1-100 nM) revealed dose-dependent induction of CAMP similar to that observed with primary cultures of human macrophages. Also consistent with macrophages, induction of trophoblastic CAMP was enhanced via intracrine conversion of 25OHD to 1,25(OH)(2)D. However, in contrast to macrophages, induction of CAMP by vitamin D in trophoblasts was not enhanced by costimulation with Toll-like receptor ligands, such as lipopolysaccharide. Despite this, exposure to vitamin D metabolites significantly enhanced antibacterial responses in trophoblastic cells: 3A cells infected with Escherichia coli showed decreased numbers of bacterial colony-forming units compared with vehicle-treated controls when treated with 25OHD (49.6% +/- 10.9%) or 1,25(OH)(2)D (45.4% +/- 9.2%), both P < 0.001. Treatment with 25OHD (1-100 nM) or 1,25(OH)(2)D (0.1-10 nM) also protected 3A cells against cell death following infection with E. coli (13.6%-26.9% and 22.3%-40.2% protection, respectively). These observations indicate that 1,25(OH)(2)D can function as an intracrine regulator of CAMP in trophoblasts, and may thus provide a novel mechanism for activation of innate immune responses in the placenta.
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: N
authors.initials: N
authors.lastname: Liu
authors.forename: A T
authors.initials: AT
authors.lastname: Kaplan
authors.forename: J
authors.initials: J
authors.lastname: Low
authors.forename: L
authors.initials: L
authors.lastname: Nguyen
authors.forename: G Y
authors.initials: GY
authors.lastname: Liu
authors.forename: O
authors.initials: O
authors.lastname: Equils
authors.forename: M
authors.initials: M
authors.lastname: Hewison
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000517:prevention & control; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism* / Q000382:microbiology; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D051193:Toll-Like Receptors; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; C104450:25-hydroxyvitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D054804:Cathelicidins