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Submitted on December 16, 2005
Accepted on February 8, 2006
Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response
Philip T. Liu 1, Steffen Stenger 2, Huiying Li 3, Linda Wenzel 2, Belinda H. Tan 1, Stephan Krutzik 4, Maria Teresa Ochoa 4, Jürgen Schauber 5, Kent Wu 6, Christoph Meinken 2, Diane L. Kamen 7, Manfred Wagner 8, Robert Bals 9, Andreas Steinmeyer 10, Ulrich Zügel 11, Richard L. Gallo 5, David Eisenberg 3, Martin Hewison 12, Bruce W. Hollis 13, John S. Adams 12, Barry R. Bloom 14, Robert L. Modlin 1*
1 Department of Microbiology, Immunology and Molecular Genetics; Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA 90095, USA. 2 Institut für Klinische Mikrobiologie, Immunologie, und Hygiene, Universität Erlangen, D-91054 Erlangen, Germany. 3 Department of Chemistry and Biological Chemistry, Howard Hughes Medical Institute, Department of Energy Institute of Genomics and Proteomics, UCLA, Los Angeles, CA 90095, USA. 4 Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA 90095, USA. 5 Division of Dermatology, University of California San Diego, and VA San Diego Healthcare Center, San Diego, CA 92161, USA. 6 Department of Microbiology, Immunology and Molecular Genetics 7 Department of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA. 8 Klinikum Nürnberg, Medizinische Klinik 3, D-90340 Nürnberg, Germany. 9 Pneumologie, Universität Marburg, D-35043 Marburg, Germany. 10 Medicinal Chemistry 11 Corporate Research Business Area (CRBA) Dermatology, Schering AG, D-13342 Berlin, Germany. 12 Department of Medicine, Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. 13 Departments of Pediatrics, Biochemistry, and Molecular Biology, MUSC, Charleston, SC 29425, USA. 14 Harvard School of Public Health, Boston, MA 02115, USA.
* To whom correspondence should be addressed.
Robert L. Modlin , E-mail: rmodlin{at}mednet.ucla.edu
In innate immune responses, activation of Toll-like receptors(TLRs) triggers direct antimicrobial activity against intracellularbacteria, which in murine, but not human, monocytes and macrophagesis mediated principally by nitric oxide. We report here thatTLR-activation of human macrophages up-regulated expressionof the vitamin D receptor and the vitamin D1-hydroxylase genes,leading to induction of the antimicrobial peptide cathelicidinand killing of intracellular Mycobacterium tuberculosis. Wealso observed that sera from African-American individuals, knownto have increased susceptibility to tuberculosis, had low 25-hydroxyvitaminD and were inefficient in supporting cathelicidin messengerRNA induction. These data support a link between TLRs and vitaminD-mediated innate immunity and suggest that differences in abilityof human populations to produce vitamin D may contribute tosusceptibility to microbial infection.
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|Full Text »|PDF »
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S. D. Chakravarty, J. Xu, B. Lu, C. Gerard, J. Flynn, and J. Chan (2007)
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|Abstract »|Full Text »|PDF »
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K. L. Munger, L. I. Levin, B. W. Hollis, N. S. Howard, and A. Ascherio (2006)
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|Abstract »|Full Text »|PDF »
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|Full Text »|PDF »
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|Abstract »|Full Text »|PDF »
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103, 11736-11741
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Am. J. Clinical Nutrition
84, 18-28
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