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IFN-- and TNF-Independent Vitamin D-Inducible Human Suppression of Mycobacteria: The Role of Cathelicidin LL-37¹

Adrian R. Martineau^*,,, Katalin A. Wilkinson^*,, Sandra M. Newton^*, R. Andres Floto, Anthony W. Norman^¶, Keira Skolimowska^*,, Robert N. Davidson^||, Ole E. Sørensen^#, Beate Kampmann^*,, Christopher J. Griffiths and Robert J. Wilkinson^2,*,,||,**

^* 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; VDR_mem, membrane-bound VDR; VDR_nuc, nuclear receptor VDR; 1-hydroxylase, 25-hydroxyvitamin D 1-hydroxylase.

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