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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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Journal of Immunology
volume
178
issue
11
pages
7190 - 7198
publisher
American Association of Immunologists
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  • wos:000246896300060
ISSN
1550-6606
language
English
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yes
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478483fa-bca0-4214-89a8-e5d31ad4e2ed (old id 650800)
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http://www.jimmunol.org/cgi/content/abstract/178/11/7190
date added to LUP
2007-12-13 13:32:16
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2016-04-16 04:52:07
@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},
  volume       = {178},
  year         = {2007},
}