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Originally published in Science Express on 23 February 2006
Science 24 March 2006:
Vol. 311. no. 5768, pp. 1770 - 1773
DOI: 10.1126/science.1123933
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Reports

Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response

Philip T. Liu,1,2* Steffen Stenger,4* Huiying Li,3 Linda Wenzel,4 Belinda H. Tan,1,2 Stephan R. Krutzik,2 Maria Teresa Ochoa,2 Jürgen Schauber,5 Kent Wu,1 Christoph Meinken,4 Diane L. Kamen,6 Manfred Wagner,7 Robert Bals,8 Andreas Steinmeyer,9 Ulrich Zügel,10 Richard L. Gallo,5 David Eisenberg,3 Martin Hewison,11 Bruce W. Hollis,12 John S. Adams,11 Barry R. Bloom,13 Robert L. Modlin1,2{dagger}

In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1–hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D–mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

1 Department of Microbiology, Immunology, and Molecular Genetics; University of California at Los Angeles, Los Angeles, CA 90095, USA.
2 Division of Dermatology, Department of Medicine, David Geffen School of Medicine; University of California at Los Angeles, Los Angeles, CA 90095, USA.
3 Department of Chemistry and Biological Chemistry, Howard Hughes Medical Institute; and Department of Energy Institute of Genomics and Proteomics, University of California at Los Angeles, Los Angeles, CA 90095, USA.
4 Institut für Klinische Mikrobiologie, Immunologie, und Hygiene, Universität Erlangen, D-91054 Erlangen, Germany.
5 Division of Dermatology, University of California at San Diego, and Veterans Affairs San Diego Healthcare Center, San Diego, CA 92161, USA.
6 Department of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
7 Klinikum Nürnberg, Medizinische Klinik 3, D-90340 Nürnberg, Germany.
8 Pneumologie, Universität Marburg, D-35043 Marburg, Germany.
9 Medicinal Chemistry, Schering AG, D-13342 Berlin, Germany.
10 Corporate Research Business Area (CRBA) Dermatology, Schering AG, D-13342 Berlin, Germany.
11 Department of Medicine, Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
12 Departments of Pediatrics, Biochemistry, and Molecular Biology, MUSC, Charleston, SC 29425, USA.
13 Harvard School of Public Health, Boston, MA 02115, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: rmodlin{at}mednet.ucla.edu

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K. L. Munger, L. I. Levin, B. W. Hollis, N. S. Howard, and A. Ascherio (2006)
JAMA 296, 2832-2838
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Effects of 25-Hydroxyvitamin D3 and 1,25-Dihydroxyvitamin D3 on Cytokine Production by Human Decidual Cells.
K. N. Evans, L. Nguyen, J. Chan, B. A. Innes, J. N. Bulmer, M. D. Kilby, and M. Hewison (2006)
Biol Reprod 75, 816-822
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The clinical and immunological features of leprosy.
S. L. Walker and D. N. J. Lockwood (2006)
Br. Med. Bull.
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Vitamin D3-Triggered Antimicrobial Response--Another Pleiotropic Effect beyond Mineral and Bone Metabolism: Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response. Science 311: 1770-1773, 2006.
P.T. Liu, S. Stenger, H. Li, L. Wenzel, B.H. Tan, S.R. Krutzik, M.T. Ochoa, J. Schauber, K. Wu, C. Meinken, et al. (2006)
J. Am. Soc. Nephrol. 17, 2949-2953
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Release of LL-37 by Activated Human V{gamma}9V{delta}2 T Cells: A Microbicidal Weapon against Brucella suis.
S. Dudal, C. Turriere, S. Bessoles, P. Fontes, F. Sanchez, J. Liautard, J.-P. Liautard, and V. Lafont (2006)
J. Immunol. 177, 5533-5539
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Vitamin D deficiency during pregnancy: an ongoing epidemic..
B. W Hollis and C. L Wagner (2006)
Am. J. Clinical Nutrition 84, 273
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Macrophages Acquire Neutrophil Granules for Antimicrobial Activity against Intracellular Pathogens.
B. H. Tan, C. Meinken, M. Bastian, H. Bruns, A. Legaspi, M. T. Ochoa, S. R. Krutzik, B. R. Bloom, T. Ganz, R. L. Modlin, et al. (2006)
J. Immunol. 177, 1864-1871
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Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis.
M. Li, P. Hener, Z. Zhang, S. Kato, D. Metzger, and P. Chambon (2006)
PNAS 103, 11736-11741
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Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
H. A Bischoff-Ferrari, E. Giovannucci, W. C Willett, T. Dietrich, and B. Dawson-Hughes (2006)
Am. J. Clinical Nutrition 84, 18-28
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