title: Interleukin 13 exposure enhances vitamin D-mediated expression of the human cathelicidin antimicrobial peptide 18/LL-37 in bronchial epithelial cells.
abstract: Vitamin D is an important regulator of the expression of antimicrobial peptides, and vitamin D deficiency is associated with respiratory infections. Regulating expression of antimicrobial peptides, such as the human cathelicidin antimicrobial peptide 18 (hCAP18)/LL-37, by vitamin D in bronchial epithelial cells requires local conversion of 25(OH)-vitamin D(3) (25D(3)) into its bioactive metabolite, 1,25(OH)(2)-vitamin D(3) (1,25D(3)), by CYP27B1. Low circulating vitamin D levels in childhood asthma are associated with more-severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2-driven inflammation mediated by cytokines such as interleukin 4 (IL-4) and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP18/LL-37 expression is unknown. Therefore, we investigated this with well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D(3), and expression of hCAP18/LL-37, CYP27B1, the 1,25D(3)-inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D(3) to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas vitamin D receptor (VDR) expression was not significantly affected. The enhancing effect of IL-13 on 25D(3)-mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western blotting and immunofluorescence staining. In conclusion, we demonstrate that IL-13 induces vitamin D-dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. j.a.schrumpf@lumc.nl
authors.forename: J A
authors.initials: JA
authors.lastname: Schrumpf
authors.forename: M A J A
authors.initials: MA
authors.lastname: van Sterkenburg
authors.forename: R M
authors.initials: RM
authors.lastname: Verhoosel
authors.forename: S
authors.initials: S
authors.lastname: Zuyderduyn
authors.forename: P S
authors.initials: PS
authors.lastname: Hiemstra
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D054804:Cathelicidins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D018793:Interleukin-13; D018167:Receptors, Calcitriol; D014807:Vitamin D; D002762:Cholecalciferol