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Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response
Abstract
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.
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“Activation of Toll-like receptor 1 (TLR1) and TLR2 by tuberculosis enhances 1α-hydroxylase expression, the enzyme mediates the synthesis of 1,25(OH)2D3, production of antimicrobial peptide cathelicidin [87], and induction of tolerogenic DCs and T cells [60,84].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [87]
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“The expression of this latter receptor as well as the vitamin D converting hydroxylases, mainly vitamin D-1 hydroxylase CYP27b1, is induced after TLR2 activation of human monocytes/macrophages (82).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [82]
In the citing paper
“Induction of cathelicidin in human keratinocytes and monocytes in skin wounds or upon infection is enhanced by 1,25 vitamin D3.42,43”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [42]
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“Induction of cathelicidin in human keratinocytes and monocytes in skin wounds or upon infection is enhanced by 1,25 vitamin D3.(42,43) Interestingly, induction of cathelicidin by 1,25 vitamin D3 in murine cells is absent probably due to the absence of a vitamin D-responsive element in the murine cathelicidin promoter.”
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Metadata
- Authors
- Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., Ochoa, M. T., Schauber, J., Wu, K., Meinken, C., Kamen, D. L., Wagner, M., Bals, R., Steinmeyer, A., Zügel, U., Gallo, R. L., Eisenberg, D., Hewison, M., Hollis, B. W., Adams, J. S., Bloom, B. R., & Modlin, R. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Department of Microbiology, Immunology, and Molecular Genetics; University of California at Los Angeles, Los Angeles, CA 90095, USA.
- Corresponding author
- Liu, Philip T.
- Stenger, Steffen
- Modlin, Robert L.
- ORCID
- Venue
- Science
- Published
- 2006-03-24
- Volume
- 311
- Issue
- 5768
- Pages
- 1770-1773
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2124580054
- Cited by
- 3,924
- References
- 24
- Citations by year
- 2026: 80 · 2025: 126 · 2024: 101 · 2023: 197 · 2022: 185 · 2021: 222 · 2020: 213 · 2019: 171 · 2018: 181 · 2017: 215 · 2016: 217 · 2015: 239 · 2014: 252 · 2013: 221 · 2012: 266
- FWCI
- 67.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI48176, AI-22553, R21AI048176, K22AI085025, AI 47868, AI 052453)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 45676, R01AR045676, AR50626, R01AR050626)
- National Center for Research Resources (RR00425, M01RR000425)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD043921, R01HD043921)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Keywords
- Toll-like receptors, vitamin D, vitamin D receptor, 25-hydroxyvitamin D, cathelicidin, antimicrobial peptides, Mycobacterium tuberculosis, human macrophages, innate immunity, tuberculosis susceptibility, African American population, intracellular bacterial killing
- MeSH terms
- Black or African American, Calcitriol, Dendritic Cells, Disease Susceptibility, Humans, Immunity, Innate, Macrophages, Monocytes, Mycobacterium tuberculosis, RNA, Messenger, Steroid Hydroxylases, Tuberculosis, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Colony Count, Microbial, Up-Regulation, Receptors, Calcitriol, Oligonucleotide Array Sequence Analysis, Antimicrobial Cationic Peptides, Toll-Like Receptors, Cathelicidins, Vitamin D3 24-Hydroxylase
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