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- and TNF-Independent Vitamin D-Inducible Human Suppression of Mycobacteria: The Role of Cathelicidin LL-371
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* Wellcome Trust Center for Research in Clinical Tropical Medicine, Division of Medicine, Wright Fleming Institute, Imperial College London, United Kingdom;
Centre for Health Sciences, Queen Mary’s School of Medicine and Dentistry, Barts and The London, London, United Kingdom;
Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa;
Department of Medicine, Cambridge Institute for Medical Research, Cambridge, United Kingdom;
¶ Department of Biochemistry, University of California, Riverside, CA 92521;
|| North West London Hospitals National Health Service Trust, Northwick Park Hospital, Harrow, United Kingdom;
# Section of Clinical and Experimental Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden; and
** Department of Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa
Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1
,25 dihydroxyvitamin D3 (1,25(OH)2D3), has pleiotropic immune effects. The mechanisms by which 1,25(OH)2D3 protects against tuberculosis are incompletely understood. 1,25(OH)2D3 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. 1,25(OH)2D3 reduced transcription and secretion of protective IFN-
, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1,25(OH)2D3 does not mediate protection via these cytokines. Although NOS2A was up-regulated by 1,25(OH)2D3, inhibition of NO formation marginally affected the suppressive effect of 1,25(OH)2D3 on bacillus Calmette Guérin in infected cells. By contrast, 1,25(OH)2D3 strongly up-regulated the cathelicidin hCAP-18 gene, and some hCAP-18 polypeptide colocalized with CD14 in 1,25(OH)2D3 stimulated PBMC, although no detectable LL-37 peptide was found in supernatants from similar 1,25(OH)2D3-stimulated PBMC cultures. A total of 200 µg/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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Wellcome Trust and the Department of Environmental Health, London Borough of Newham.
2 Address correspondence and reprint requests to Dr. Robert Wilkinson, Imperial College London and University of Cape Town, Wernher and Beit South Building, Faculty of Health Science, Observatory, South Africa. E-mail address: r.j. wilkinson{at}imperial.ac.uk
3 Abbreviations used in this paper: TB, tuberculosis; 1,25(OH)2D3, 1,25 dihydroxyvitamin D3; 25(OH)D3, 25-hydroxyvitamin D3; BCG, bacillus Calmette Guérin; L-NMMA, L-NG-monomethylarginine; LR, luminescence ratio; MN, monocyte; MOI, multiplicity of infection; PS, permeabilization solution; RLU, relative luciferase unit; RNI, reactive nitrogen intermediate; VDR, vitamin D receptor; VDRmem, membrane-bound VDR; VDRnuc, nuclear receptor VDR; 1-hydroxylase, 25-hydroxyvitamin D 1-hydroxylase.
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