IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37.
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.
Martineau
Adrian R
AR
Wellcome Trust Center for Research in Clinical Tropical Medicine, Division of Medicine, Wright Fleming Institute, Imperial College London, United Kingdom.
Wilkinson
Katalin A
KA
Newton
Sandra M
SM
Floto
R Andres
RA
Norman
Anthony W
AW
Skolimowska
Keira
K
Davidson
Robert N
RN
Sørensen
Ole E
OE
Kampmann
Beate
B
Griffiths
Christopher J
CJ
Wilkinson
Robert J
RJ
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
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D006131:Growth Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002117:Calcitriol; D054804:Cathelicidins