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IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: The role of cathelicidin LL-37

Martineau, Adrian R. ; Wilkinson, Katalin A. ; Newton, Sandra M. ; Floto, R. Andres ; Norman, Anthony W. ; Skolimowska, Keira ; Davidson, Robert N. ; Sørensen, Ole E LU ; Kampmann, Beate and Griffiths, Christopher J. , et al. (2007) In Journal of Immunology 178(11). p.7190-7198
Abstract
Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1 alpha,25 dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3), has pleiotropic immune effects. The mechanisms by which 1 alpha,25(OH)(2)D-3 protects against tuberculosis are incompletely understood. 1 alpha,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. 1 alpha,25(OH)(2)D-3 reduced transcription and secretion of protective IFN-gamma, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1... (More)
Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1 alpha,25 dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3), has pleiotropic immune effects. The mechanisms by which 1 alpha,25(OH)(2)D-3 protects against tuberculosis are incompletely understood. 1 alpha,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. 1 alpha,25(OH)(2)D-3 reduced transcription and secretion of protective IFN-gamma, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1 alpha,25(OH)(2)D-3 does not mediate protection via these cytokines. Although NOM was up-regulated by 1 alpha,25(OH)(2)D-3, inhibition of NO formation marginally affected the suppressive effect of 1 alpha,25(OH)(2)D-3 on bacillus Calmette Guerin in infected cells. By contrast, 1 alpha,25(OH)(2)D-3 strongly up-regulated the cathelicidin hCAP-18 gene, and some hCAP-18 polypeptide colocalized with CD14 in 1 alpha,25(OH)(2)D-3 stimulated PBMC, although no detectable LL-37 peptide was found in supernatants from similar 1 alpha,25(OH)(2)D-3-stimulated PBMC cultures. A total of 200 mu g/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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
178
issue
11
pages
7190 - 7198
publisher
American Association of Immunologists
external identifiers
  • wos:000246896300060
ISSN
1550-6606
language
English
LU publication?
yes
id
478483fa-bca0-4214-89a8-e5d31ad4e2ed (old id 650800)
alternative location
http://www.jimmunol.org/cgi/content/abstract/178/11/7190
date added to LUP
2016-04-01 16:46:46
date last changed
2018-11-21 20:44:08
@article{478483fa-bca0-4214-89a8-e5d31ad4e2ed,
  abstract     = {{Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1 alpha,25 dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3), has pleiotropic immune effects. The mechanisms by which 1 alpha,25(OH)(2)D-3 protects against tuberculosis are incompletely understood. 1 alpha,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. 1 alpha,25(OH)(2)D-3 reduced transcription and secretion of protective IFN-gamma, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1 alpha,25(OH)(2)D-3 does not mediate protection via these cytokines. Although NOM was up-regulated by 1 alpha,25(OH)(2)D-3, inhibition of NO formation marginally affected the suppressive effect of 1 alpha,25(OH)(2)D-3 on bacillus Calmette Guerin in infected cells. By contrast, 1 alpha,25(OH)(2)D-3 strongly up-regulated the cathelicidin hCAP-18 gene, and some hCAP-18 polypeptide colocalized with CD14 in 1 alpha,25(OH)(2)D-3 stimulated PBMC, although no detectable LL-37 peptide was found in supernatants from similar 1 alpha,25(OH)(2)D-3-stimulated PBMC cultures. A total of 200 mu g/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.}},
  author       = {{Martineau, Adrian R. and Wilkinson, Katalin A. and Newton, Sandra M. and Floto, R. Andres and Norman, Anthony W. and Skolimowska, Keira and Davidson, Robert N. and Sørensen, Ole E and Kampmann, Beate and Griffiths, Christopher J. and Wilkinson, Robert J.}},
  issn         = {{1550-6606}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{7190--7198}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of Immunology}},
  title        = {{IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: The role of cathelicidin LL-37}},
  url          = {{http://www.jimmunol.org/cgi/content/abstract/178/11/7190}},
  volume       = {{178}},
  year         = {{2007}},
}