title: Proinflammatory Cytokines Impair Vitamin D-Induced Host Defense in Cultured Airway Epithelial Cells.
abstract: Vitamin D is a regulator of host defense against infections and induces expression of the antimicrobial peptide hCAP18/LL-37. Vitamin D deficiency is associated with chronic inflammatory lung diseases and respiratory infections. However, it is incompletely understood if and how (chronic) airway inflammation affects vitamin D metabolism and action. We hypothesized that long-term exposure of primary bronchial epithelial cells to proinflammatory cytokines alters their vitamin D metabolism, antibacterial activity, and expression of hCAP18/LL-37. To investigate this, primary bronchial epithelial cells were differentiated at the air-liquid interface for 14 days in the presence of the proinflammatory cytokines, TNF-α and IL-1β (TNF-α/IL-1β), and subsequently exposed to vitamin D (inactive 25(OH)D3and active 1,25(OH)2D3). Expression of hCAP18/LL-37, vitamin D receptor, and enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) was determined using quantitative PCR, Western blot, and immunofluorescence staining. Furthermore, vitamin D-mediated antibacterial activity was assessed using nontypeable Haemophilus influenzae. We found that TNF-α/IL-1β treatment reduced vitamin D-induced expression of hCAP18/LL-37 and killing of nontypeable H. influenzae. In addition, CYP24A1 (a vitamin D-degrading enzyme) was increased by TNF-α/IL-1β, whereas CYP27B1 (that converts 25(OH)D3to its active form) and vitamin D receptor expression remained unaffected. Furthermore, we have demonstrated that the TNF-α/IL-1β-mediated induction of CYP24A1 was, at least in part, mediated by the transcription factor specific protein 1, and the epidermal growth factor receptor-mitogen-activated protein kinase pathway. These findings indicate that TNF-α/IL-1β decreases vitamin D-mediated antibacterial activity and hCAP18/LL-37 expression via induction of CYP24A1 and suggest that chronic inflammation impairs protective responses induced by vitamin D.
authors.affiliation: 1 Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands; and.
authors.forename: Jasmijn A
authors.initials: JA
authors.lastname: Schrumpf
authors.affiliation: 1 Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands; and.
authors.forename: Gimano D
authors.initials: GD
authors.lastname: Amatngalim
authors.affiliation: 1 Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands; and.
authors.forename: Joris B
authors.initials: JB
authors.lastname: Veldkamp
authors.affiliation: 1 Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands; and.
authors.forename: Renate M
authors.initials: RM
authors.lastname: Verhoosel
authors.affiliation: 1 Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands; and.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Ninaber
authors.affiliation: 2 Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Soledad R
authors.initials: SR
authors.lastname: Ordonez
authors.affiliation: 1 Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands; and.
authors.forename: Anne M
authors.initials: AM
authors.lastname: van der Does
authors.affiliation: 2 Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Henk P
authors.initials: HP
authors.lastname: Haagsman
authors.affiliation: 1 Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands; and.
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology; D023181:Antimicrobial Cationic Peptides; D001980:Bronchi / Q000166:cytology*; D002112:Calcifediol / Q000494:pharmacology; D054804:Cathelicidins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006193:Haemophilus influenzae / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D020381:Interleukin-17 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D050296:Microbial Viability / Q000187:drug effects; D009077:Mucins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014807:Vitamin D / Q000494:pharmacology*; D065668:Vitamin D3 24-Hydroxylase / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17; D053583:Interleukin-1beta; D009077:Mucins; D016329:Sp1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D014807:Vitamin D; D065668:Vitamin D3 24-Hydroxylase; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D002112:Calcifediol
keywords: airway epithelial cells; hCAP18/LL-37; host defense; proinflammatory mediators; vitamin D