IFN-γ- and TNF-Independent Vitamin D-Inducible Human Suppression of Mycobacteria: The Role of Cathelicidin LL-37
Open accessAbstract
Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1α,25 dihydroxyvitamin D3 (1α,25(OH)2D3), has pleiotropic immune effects. The mechanisms by which 1α,25(OH)2D3 protects against tuberculosis are incompletely understood. 1α,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. 1α,25(OH)2D3 reduced transcription and secretion of protective IFN-γ, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1α,25(OH)2D3 does not mediate protection via these cytokines. Although NOS2A was up-regulated by 1α,25(OH)2D3, inhibition of NO formation marginally affected the suppressive effect of 1α,25(OH)2D3 on bacillus Calmette Guérin in infected cells. By contrast, 1α,25(OH)2D3 strongly up-regulated the cathelicidin hCAP-18 gene, and some hCAP-18 polypeptide colocalized with CD14 in 1α,25(OH)2D3 stimulated PBMC, although no detectable LL-37 peptide was found in supernatants from similar 1α,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 claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TLR2-induced vitamin D receptor signaling results in increased expression of target genes containing vitamin D response elements, such as the anti-microbial peptide cathelicidin (LL37).
“This results in increased expression of target genes containing vitamin D response elements within their promoter regions, such as the anti-microbial peptide cathelicidin (LL37) (83).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [83]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response
Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., Ochoa, M. T., Schauber, J., Wu, K., Meinken, C., et al. (2006) · Science · doi:10.1126/science.1123933 · Cited by 3,924 · see citing works
Tuberculosis Associated with Infliximab, a Tumor Necrosis Factor α–Neutralizing Agent
Keane, J., Gershon, S. K., Wise, R. P., Mirabile‐Levens, E., Kasznica, J. M., Schwieterman, W. D., Siegel, J. N., & Braun, M. M. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa011110 · Cited by 3,698 · see citing works
The Growing Burden of Tuberculosis: <b>Global Trends and Interactions With the HIV Epidemic</b>
Corbett, E. L., Watt, C. J., Walker, N., Maher, D., Williams, B. G., Raviglione, M. C., & Dye, C. (2003) · Archives of Internal Medicine · doi:10.1001/archinte.163.9.1009 · Cited by 2,553 · see citing works
Cutting Edge: 1,25-Dihydroxyvitamin D3 Is a Direct Inducer of Antimicrobial Peptide Gene Expression
Wang, T. T., Nestel, F. P., Bourdeau, V., Nagai, Y., Wang, Q., Liao, J. L., Tavera-Mendoza, L. E., Lin, R., Hanrahan, J. W., Mader, S., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.5.2909 · Cited by 1,640 · see citing works
Yang, D., Chen, Q., Schmidt, A. P., Anderson, G. M., Wang, J., Wooters, J., Oppenheim, J. J., & Chertov, O. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.7.1069 · Cited by 1,238 · see citing works
A Mutation in the Interferon-γ –Receptor Gene and Susceptibility to Mycobacterial Infection
Newport, M. J., Huxley, C. M., Huston, S., Hawrylowicz, C. M., Oostra, B. A., Williamson, R., & Levin, M. (1996) · New England Journal of Medicine · doi:10.1056/nejm199612263352602 · Cited by 1,198 · see citing works
Identification of nitric oxide synthase as a protective locus against tuberculosis
MacMicking, J. D., North, R. J., LaCourse, R., Mudgett, J. S., Shah, S. K., & Nathan, C. F. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5243 · Cited by 1,180 · see citing works
Flynn, J., & Chan, J. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.19.1.93 · Cited by 1,144 · see citing works
Sørensen, O. E., Follin, P., Johnsen, A. H., Calafat, J., Tjabringa, G. S., Hiemstra, P. S., & Borregaard, N. (2001) · Blood · doi:10.1182/blood.v97.12.3951 · Cited by 894 · see citing works
Self-citationImpairment of Mycobacterial Immunity in Human Interleukin-12 Receptor Deficiency
Altare, F., Durandy, A., Lammas, D. A., Emile, J., Lamhamedi‐Cherradi, S., Deist, F. L., Drysdale, P., Jouanguy, E., Döffinger, R., Bernaudin, F., et al. (1998) · Science · doi:10.1126/science.280.5368.1432 · Cited by 843 · see citing works
Wilkinson, R. J., Llewelyn, M., Toossi, Z., Patel, P., Pasvol, G., Lalvani, A., Wright, D. J., Latif, M., & Davidson, R. N. (2000) · The Lancet · doi:10.1016/s0140-6736(99)02301-6 · Cited by 768 · see citing works
Self-citationThe Human Antimicrobial Peptide LL-37 Is a Multifunctional Modulator of Innate Immune Responses
Scott, M. G., Davidson, D. J., Gold, M. R., Bowdish, D. M. E., & Hancock, R. E. W. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.7.3883 · Cited by 713 · see citing works
Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47
MacMicking, J. D., Taylor, G. A., & McKinney, J. D. (2003) · Science · doi:10.1126/science.1088063 · Cited by 685 · see citing works
(1992) · International Journal of Biochemistry · doi:10.1016/0020-711x(92)90281-5 · Cited by 673 · see citing works
Global Trends in Resistance to Antituberculosis Drugs
Espinal, M., Laszlo, A., Simonsen, L., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200104263441706 · Cited by 673 · see citing works
Rook, G. A. W., Steele, J. K., Fraher, L. J., Barker, S. C., Karmali, R., O'Riordan, J. L. H., & Stanford, J. L. (1986) · PubMed Central · Cited by 529 · see citing works
(1984) · British Journal of Diseases of the Chest · doi:10.1016/0007-0971(84)90110-4 · Cited by 498 · see citing works
Corbett, E. L., Marston, B. J., Churchyard, G., & Cock, K. M. D. (2006) · The Lancet · doi:10.1016/s0140-6736(06)68383-9 · Cited by 438 · see citing works
Bellamy, R., Ruwende, C., Corrah, T., Mcadam, K. P. W. J., Thursz, M. R., Whittle, H., & Hill, A. V. S. (1999) · The Journal of Infectious Diseases · doi:10.1086/314614 · Cited by 436 · see citing works
Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000
Joint Tuberculosis Committee of the British Thoracic Society (2000) · Thorax · doi:10.1136/thorax.55.11.887 · Cited by 374 · see citing works
Iron, mycobacteria and tuberculosis
Ratledge, C. (2003) · Tuberculosis · doi:10.1016/j.tube.2003.08.012 · Cited by 344 · see citing works
Rockett, K. A., Brookes, R. H., Udalova, I. A., Vidal, V., Hill, A. V. S., & Kwiatkowski, D. P. (1998) · Infection and Immunity · doi:10.1128/iai.66.11.5314-5321.1998 · Cited by 306 · see citing works
Tuberculosis Among Foreign-Born Persons in the United States
Cain, K. P., Benoit, S. R., Winston, C. A., & Kenzie, W. R. M. (2008) · JAMA · doi:10.1001/jama.300.4.405 · Cited by 295 · see citing works
Perturbation of the Hydrophobic Core of Lipid Bilayers by the Human Antimicrobial Peptide LL-37
Henzler‐Wildman, K. A., Martinez, G. V., Brown, M. F., & Ramamoorthy, A. (2004) · Biochemistry · doi:10.1021/bi036284s · Cited by 295 · see citing works
Bekpen, C., Hunn, J. P., Rohde, C., Parvanova, I., Guethlein, L., Dunn, D. M., Glowalla, E., Leptin, M., & Howard, J. C. (2005) · Genome biology · doi:10.1186/gb-2005-6-11-r92 · Cited by 294 · see citing works
Immune Regulation of 25-Hydroxyvitamin-D3-1α-Hydroxylase in Human Monocytes
Stoffels, K., Overbergh, L., Giulietti, A., Verlinden, L., Bouillon, R., & Mathieu, C. (2006) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.050908 · Cited by 256 · see citing works
Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-γ
Kampmann, B., Hemingway, C. A., Stephens, A. C., Davidson, R. N., Goodsall, A. L., Anderson, S. T. B., Nicol, M. P., Schölvinck, E. H., Relman, D. A., Waddell, S. J., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci19316 · Cited by 251 · see citing works
Self-citationCrowle, A. J., Ross, E., & May, M. H. (1987) · Infection and Immunity · doi:10.1128/iai.55.12.2945-2950.1987 · Cited by 241 · see citing works
Sly, L. M., Lopez, M., Nauseef, W. M., & Reiner, N. E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102876200 · Cited by 238 · see citing works
Vitamin D in the treatment of pulmonary tuberculosis
Martineau, A. R., Honecker, F. U., Wilkinson, R. J., & Griffiths, C. J. (2007) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.12.052 · Cited by 216 · see citing works
Self-citationAn ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma
Sørensen, O. E., Cowland, J. B., Askaa, J., & Borregaard, N. (1997) · Journal of Immunological Methods · doi:10.1016/s0022-1759(97)00084-7 · Cited by 209 · see citing works
Self-citationStudies of Vitamin D Deficiency in Man
Preece, M. A., Tomlinson, S., Ribot, C., et al. (1975) · QJM · doi:10.1093/oxfordjournals.qjmed.a067443 · Cited by 197 · see citing works
The mammalian ionic environment dictates microbial susceptibility to antimicrobial defense peptides
Dorschner, R. A., López‐García, B., Peschel, A., Kraus, D., Morikawa, K., Nizet, V., & Gallo, R. L. (2006) · The FASEB Journal · doi:10.1096/fj.05-4406com · Cited by 186 · see citing works
Rose, A. M. (2001) · Thorax · doi:10.1136/thorax.56.3.173 · Cited by 185 · see citing works
Norman, A. W., Bouillon, R., Farach‐Carson, M. C., Bishop, J. E., Zhou, L., Nemere, I., Zhao, J. V., Muralidharan, K. R., & OKAMURA, W. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80689-9 · Cited by 180 · see citing works
Self-citationAssessment of Immunity to Mycobacterial Infection with Luciferase Reporter Constructs
Snewin, V. A., Gares, M., Gaora, P. Ó., Hasan, Z., Brown, I. N., & Young, D. (1999) · Infection and Immunity · doi:10.1128/iai.67.9.4586-4593.1999 · Cited by 177 · see citing works
Ustianowski, A., Shaffer, R., Collin, S. M., Wilkinson, R. J., & Davidson, R. (2004) · Journal of Infection · doi:10.1016/j.jinf.2004.07.006 · Cited by 166 · see citing works
Self-citationSerum concentrations of vitamin D metabolites in untreated tuberculosis.
Davies, P. D. O., Brown, R. C., & Woodhead, J. S. (1985) · Thorax · doi:10.1136/thx.40.3.187 · Cited by 157 · see citing works
Hmama, Z., Sendide, K., Talal, A., García, R., Dobos, K. M., & Reiner, N. E. (2004) · Journal of Cell Science · doi:10.1242/jcs.01072 · Cited by 151 · see citing works
Tuberculosis Among Foreign-Born Persons in the United States, 1993-1998
Talbot, E. A. (2000) · JAMA · doi:10.1001/jama.284.22.2894 · Cited by 145 · see citing works
Vidal, M., Ramana, C. V., & Dusso, A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.8.2777-2787.2002 · Cited by 137 · see citing works
Norman, A. W., Okamura, W. H., Hammond, M. W., Bishop, J. E., Dormanen, M. C., Bouillon, R., BAELEN, H. V., Ridall, A. L., Daane, E., Khoury, R., et al. (1997) · Molecular Endocrinology · doi:10.1210/mend.11.10.9993 · Cited by 123 · see citing works
Self-citationThe Human Antibacterial Cathelicidin, hCAP-18, Is Bound to Lipoproteins in Plasma
Sørensen, O. E., Bratt, T., Johnsen, A. H., Madsen, M. T., & Borregaard, N. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.32.22445 · Cited by 118 · see citing works
Self-citationUpdate on biological actions of 1α,25(OH)2-vitamin D3 (rapid effects) and 24R,25(OH)2-vitamin D3
Norman, A. W., Okamura, W. H., Bishop, J. E., & Henry, H. L. (2002) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(02)00273-3 · Cited by 111 · see citing works
Self-citationEvaluation of Human Antimycobacterial Immunity Using Recombinant Reporter Mycobacteria
Kampmann, B., Gaora, P. Ó., Snewin, V. A., Gares, M., Young, D., & Levin, M. (2000) · The Journal of Infectious Diseases · doi:10.1086/315766 · Cited by 94 · see citing works
Self-citationZhou, L., Nemere, I., & Norman, A. W. (1992) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.5650070414 · Cited by 74 · see citing works
Self-citationInfection Biology of a Novel α-Crystallin of Mycobacterium tuberculosis: Acr2
Wilkinson, K. A., Stewart, G. R., Newton, S. M., Vordermeier, H. M., Wain, J. R., Murphy, H. N., Horner, K., Young, D., & Wilkinson, R. J. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.7.4237 · Cited by 62 · see citing works
Self-citationWilkinson, R. J., DesJardin, L. E., Islam, N., Gibson, B. M., Kanost, R. A., Wilkinson, K. A., Poelman, D., Eisenach, K. D., & Toossi, Z. (2001) · Molecular Microbiology · doi:10.1046/j.1365-2958.2001.02280.x · Cited by 52 · see citing works
Self-citationStewart, G. R., Wilkinson, K. A., Newton, S. M., Sullivan, S. M., Neyrolles, O., Wain, J. R., Patel, J., Pool, K.-L., Young, D. B., & Wilkinson, R. J. (2005) · Infection and Immunity · doi:10.1128/iai.73.10.6831-6837.2005 · Cited by 42 · see citing works
Self-citationBula, C. M., Bishop, J. E., Ishizuka, S., et al. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.11.0552 · Cited by 41 · see citing works
Wah, J., Wellek, A., Frankenberger, M., Unterberger, P., WELSCH, U. N., & Bals, R. (2006) · Cell and Tissue Research · doi:10.1007/s00441-005-0127-7 · Cited by 40 · see citing works
Turner, D. J., Hoyle, S., Snewin, V. A., et al. (2002) · Microbiology · doi:10.1099/00221287-148-10-2929 · Cited by 19 · see citing works
The development of tuberculosis in afro-Asian immigrants
Grenville‐Mathers, R., & Clark, J. B. (1979) · Tubercle · doi:10.1016/0041-3879(79)90052-7 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response
Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., Ochoa, M. T., Schauber, J., Wu, K., Meinken, C., et al. (2006) · Science · doi:10.1126/science.1123933 · Cited by 3,924 · see citing works
The P2X7 Receptor: A Key Player in IL-1 Processing and Release
Ferrari, D., Pizzirani, C., Adinolfi, E., Lemoli, R. M., Curti, A., Idzko, M., Panther, E., & Di Virgilio, F. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.7.3877 · Cited by 1,025 · see citing works
Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989 · see citing works
Crucian, B. E., Choukèr, A., Simpson, R. J., Mehta, S., Marshall, G., Smith, S. M., Zwart, S. R., Heer, M., Ponomarev, S., Whitmire, A., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01437 · Cited by 421 · see citing works
Newton, S. M., Brent, A. J., Anderson, S., Whittaker, E., & Kampmann, B. (2008) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(08)70182-8 · Cited by 480 · see citing works
Self-citationNeutrophil-mediated innate immune resistance to mycobacteria
Martineau, A. R., Newton, S. M., Wilkinson, K. A., Kampmann, B., Hall, B. M., Nawroly, N., Packe, G. E., Davidson, R. N., Griffiths, C. J., & Wilkinson, R. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31097 · Cited by 394 · see citing works
Self-citationSonawane, A., Santos, J. C., Mishra, B. B., Jena, P., Progida, C., Sorensen, O. E., Gallo, R., Appelberg, R., & Griffiths, G. (2011) · Cellular Microbiology · doi:10.1111/j.1462-5822.2011.01644.x · Cited by 165 · see citing works
Innate immunity to mycobacteria: vitamin D and autophagy
Jo, E.-K. (2010) · Cellular Microbiology · doi:10.1111/j.1462-5822.2010.01491.x · Cited by 98 · see citing works
Transcription factors and cognate signalling cascades in the regulation of autophagy
Chandra, V., Bhagyaraj, E., Parkesh, R., & Gupta, P. (2016) · Biological Reviews · doi:10.1111/brv.12177 · Cited by 26 · see citing works
- Authors
- Martineau, A. R., Wilkinson, K. A., Newton, S. M., Floto, R. A., Norman, A. W., Skolimowska, K., Davidson, R. N., Sørensen, O. E., Kampmann, B., Griffiths, C. J., & Wilkinson, R. J.
- Affiliations
- University of Cape Town (ZA)
- Imperial College London (GB)
- Department of Medicine, Cambridge Institute for Medical Research , Cambridge ,
- University of California, Riverside (US)
- National Health Service (GB)
- Lund University (SE)
- Centre for Health Sciences, Queen Mary’s School of Medicine and Dentistry, Barts and The London , London ,
- Corresponding author
- Skolimowska, Keira
- Kampmann, Beate
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-06-01
- Volume
- 178
- Issue
- 11
- Pages
- 7190-7198
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2121256372
- Cited by
- 410
- References
- 53
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 10 · 2023: 14 · 2022: 23 · 2021: 14 · 2020: 16 · 2019: 21 · 2018: 26 · 2017: 25 · 2016: 31 · 2015: 30 · 2014: 31 · 2013: 26 · 2012: 26
- FWCI
- 16.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Wellcome Trust (077273/Z/05/Z, 072070)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- vitamin D, 1,25-dihydroxyvitamin D3, tuberculosis, Mycobacterium tuberculosis, LL-37, cathelicidin, antimicrobial peptides, interferon-gamma, TNF-α, IL-12, nitric oxide, CD14, macrophages, peripheral blood mononuclear cells, bacterial growth inhibition
- MeSH terms
- Anti-Bacterial Agents, Calcitriol, Cells, Cultured, Growth Inhibitors, Humans, Interferon-gamma, Mycobacterium bovis, Mycobacterium tuberculosis, Tumor Necrosis Factor-alpha, Coculture Techniques, Antimicrobial Cationic Peptides, Cathelicidins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
