title: IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37.
abstract: Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1alpha,25 dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), has pleiotropic immune effects. The mechanisms by which 1alpha,25(OH)(2)D(3) protects against tuberculosis are incompletely understood. 1alpha,25(OH)(2)D(3) reduced the growth of mycobacteria in infected human PBMC cultures in a dose-dependent fashion. Coculture with agonists or antagonists of the membrane or nuclear vitamin D receptors indicated that these effects were primarily mediated by the nuclear vitamin D receptors. 1alpha,25(OH)(2)D(3) reduced transcription and secretion of protective IFN-gamma, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1alpha,25(OH)(2)D(3) does not mediate protection via these cytokines. Although NOS2A was up-regulated by 1alpha,25(OH)(2)D(3), inhibition of NO formation marginally affected the suppressive effect of 1alpha,25(OH)(2)D(3) on bacillus Calmette Guérin in infected cells. By contrast, 1alpha,25(OH)(2)D(3) strongly up-regulated the cathelicidin hCAP-18 gene, and some hCAP-18 polypeptide colocalized with CD14 in 1alpha,25(OH)(2)D(3) stimulated PBMC, although no detectable LL-37 peptide was found in supernatants from similar 1alpha,25(OH)(2)D(3)-stimulated PBMC cultures. A total of 200 mug/ml of the active peptide LL-37, in turn, reduced the growth of Mycobacterium tuberculosis in culture by 75.7%. These findings suggest that vitamin D contributes to protection against TB by "nonclassical" mechanisms that include the induction of antimicrobial peptides.
authors.affiliation: Wellcome Trust Center for Research in Clinical Tropical Medicine, Division of Medicine, Wright Fleming Institute, Imperial College London, United Kingdom.
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Martineau
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Newton
authors.forename: R Andres
authors.initials: RA
authors.lastname: Floto
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Norman
authors.forename: Keira
authors.initials: K
authors.lastname: Skolimowska
authors.forename: Robert N
authors.initials: RN
authors.lastname: Davidson
authors.forename: Ole E
authors.initials: OE
authors.lastname: Sørensen
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Griffiths
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000502:physiology*; D002117:Calcitriol / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D009163:Mycobacterium bovis / Q000187:drug effects / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D054804:Cathelicidins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D006131:Growth Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002117:Calcitriol; D054804:Cathelicidins