Interaction between vitamin D and the immune system has been recognized for many years, but its relevance to normal human physiology has only become evident in the past 5 years. Studies of innate immune responses to pathogens such as Mycobacterium tuberculosis have shown that pathogen-recognition receptor-mediated activation of localized vitamin D metabolism and signaling is a key event associated with infection. Vitamin D, acting in an intracrine fashion, is able to induce expression of antibacterial proteins and enhance the environment in which they function. The net effect of these actions is to support increased bacterial killing in a variety of cell types. The efficacy of such a response is highly dependent on vitamin D status; in other words, the availability of circulating 25-hydroxyvitamin D for intracrine conversion to active 1,25-dihydroxyvitamin D by the enzyme 25-hydroxyvitamin D-1α-hydroxylase. The potential importance of this mechanism as a determinant of human disease is underlined by increasing awareness of vitamin D insufficiency across the globe. This Review will explore the molecular and cellular systems associated with antibacterial responses to vitamin D in different tissues and possible consequences of such a response for the prevention and treatment of human immune disorders.
Nonclassical effects of vitamin D have been recognized for many years, but only in the past 5 years have these effects been accepted as an important component of vitamin D physiology
Immune cells, such as monocytes and macrophages, contain all the machinery required to synthesize and respond to active vitamin D, 1,25-dihydroxyvitamin D, and this machinery is enhanced by challenge to the immune system
1,25-dihydroxyvitamin D stimulates innate immune antibacterial activity in a variety of cell types by increasing production of antimicrobial factors and by enhancing mechanisms associated with autophagy
Vitamin D insufficiency is now a global health issue, even in developed countries
Vitamin D insufficiency may compromise antibacterial activity and increase the risk of infectious diseases; vitamin D may also regulate innate immune responses in noninfectious settings
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Chapuy, M. C. et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos. Int. 7, 439–443 (1997).
Heaney, R. P., Dowell, M. S., Hale, C. A. & Bendich, A. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J. Am. Coll. Nutr. 22, 142–146 (2003).
Adams, J. S. & Hewison, M. Update in vitamin D. J. Clin. Endocrinol. Metab. 95, 471–478 (2010).
Souberbielle, J. C. et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun. Rev. 9, 709–715 (2010).
Holick, M. F. Vitamin D status: measurement, interpretation, and clinical application. Ann. Epidemiol. 19, 73–78 (2009).
Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).
Holick, M. F. Vitamin D: its role in cancer prevention and treatment. Prog. Biophys. Mol. Biol. 92, 49–59 (2006).
Adams, J. S. & Hewison, M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat. Clin. Pract. Endocrinol. Metab. 4, 80–90 (2008).
Gombart, A. F., Luong, Q. T. & Koeffler, H. P. Vitamin D compounds: activity against microbes and cancer. Anticancer Res. 26, 2531–2542 (2006).
Zehnder, D. et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J. Clin. Endocrinol. Metab. 86, 888–894 (2001).
Rook, G. A. et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57, 159–163 (1986).
Bunce, C. M., Brown, G. & Hewison, M. Vitamin D and haematopoiesis. Trends Endocrinol. Metab. 8, 245–251 (1997).
Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).
Trinchieri, G. & Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7, 179–190 (2007).
Liu, P. T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).
Risso, A. Leukocyte antimicrobial peptides: multifunctional effector molecules of innate immunity. J. Leukoc. Biol. 68, 785–792 (2000).
Adams, J. S. et al. Vitamin D-directed rheostatic regulation of monocyte antibacterial responses. J. Immunol. 182, 4289–4295 (2009).
Wang, T. T. et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 173, 2909–2912 (2004).
Gombart, A. F., Borregaard, N. & Koeffler, H. P. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 19, 1067–1077 (2005).
Gombart, A. F., Saito, T. & Koeffler, H. P. Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates. BMC Genomics 10, 321 (2009).
Liu, P. T. et al. Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. PLoS ONE 4, e5810 (2009).
Kao, C. Y., Kim, C., Huang, F. & Wu, R. Requirements for two proximal NF-kappaB binding sites and IkappaB-zeta in IL-17A-induced human beta-defensin 2 expression by conducting airway epithelium. J. Biol. Chem. 283, 15309–15318 (2008).
Wang, T. T. et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn's disease. J. Biol. Chem. 285, 2227–2231 (2010).
Strober, W., Murray, P. J., Kitani, A. & Watanabe, T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat. Rev. Immunol. 6, 9–20 (2006).
Krishnan, A. V. & Feldman, D. Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment. Endocr. Relat. Cancer 17, R19–R38 (2010).
Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).
Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).
Krutzik, S. R. et al. IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway. J. Immunol. 181, 7115–7120 (2008).
Sly, L. M., Lopez, M., Nauseef, W. M. & Reiner, N. E. 1Alpha,25-dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. J. Biol. Chem. 276, 35482–35493 (2001).
Kohchi, C., Inagawa, H., Nishizawa, T. & Soma, G. ROS and innate immunity. Anticancer Res. 29, 817–821 (2009).
Chan, J., Xing, Y., Magliozzo, R. S. & Bloom, B. R. Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. J. Exp. Med. 175, 1111–1122 (1992).
Rockett, K. A. et al. 1,25-dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect. Immun. 66, 5314–5321 (1998).
Yang, C. S. et al. NADPH oxidase 2 interaction with TLR2 is required for efficient innate immune responses to mycobacteria via cathelicidin expression. J. Immunol. 182, 3696–3705 (2009).
Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 3, 710–720 (2003).
Klionsky, D. J. & Emr, S. D. Autophagy as a regulated pathway of cellular degradation. Science 290, 1717–1721 (2000).
Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).
Deretic, V. & Levine, B. Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5, 527–549 (2009).
Høyer-Hansen, M., Bastholm, L., Mathiasen, I. S., Elling, F. & Jäättelä, M. Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ. 12, 1297–1309 (2005).
Wang, J., Lian, H., Zhao, Y., Kauss, M. A. & Spindel, S. Vitamin D3 induces autophagy of human myeloid leukemia cells. J. Biol. Chem. 283, 25596–25605 (2008).
Yuk, J. M. et al. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe 6, 231–243 (2009).
Shin, D. M. et al. Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signaling. Cell. Microbiol. 12, 1648–1665 (2010).
O'Kelly, J., Uskokovic, M., Lemp, N., Vadgama, J. & Koeffler, H. P. Novel Gemini-vitamin D3 analog inhibits tumor cell growth and modulates the Akt/mTOR signaling pathway. J. Steroid Biochem. Mol. Biol. 100, 107–116 (2006).
Sanjuan, M. A., Milasta, S. & Green, D. R. Toll-like receptor signaling in the lysosomal pathways. Immunol. Rev. 227, 203–220 (2009).
Takahashi, K. et al. Human neutrophils express messenger RNA of vitamin D receptor and respond to 1alpha,25-dihydroxyvitamin D3. Immunopharmacol. Immunotoxicol. 24, 335–347 (2002).
Sørensen, O., Cowland, J. B., Askaa, J. & Borregaard, N. An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma. J. Immunol. Methods 206, 53–59 (1997).
Schauber, J. et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J. Clin. Invest. 117, 803–811 (2007).
Nijnik, A., Pistolic, J., Wyatt, A., Tam, S. & Hancock, R. E. Human cathelicidin peptide LL-37 modulates the effects of IFN-gamma on APCs. J. Immunol. 183, 5788–5798 (2009).
Carretero, M. et al. In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37. J. Invest. Dermatol. 128, 223–236 (2008).
Schauber, J. & Gallo, R. L. Expanding the roles of antimicrobial peptides in skin: alarming and arming keratinocytes. J. Invest. Dermatol. 127, 510–512 (2007).
Ong, P. Y. et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160 (2002).
Evans, K. N. et al. Effects of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on cytokine production by human decidual cells. Biol. Reprod. 75, 816–822 (2006).
Liu, N. et al. Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway. Biol. Reprod. 80, 398–406 (2009).
Zehnder, D. et al. The ontogeny of 25-hydroxyvitamin D(3) 1alpha-hydroxylase expression in human placenta and decidua. Am. J. Pathol. 161, 105–114 (2002).
Evans, K. N., Bulmer, J. N., Kilby, M. D. & Hewison, M. Vitamin D and placental-decidual function. J. Soc. Gynecol. Investig. 11, 263–271 (2004).
King, A. E. et al. Expression of natural antimicrobials by human placenta and fetal membranes. Placenta 28, 161–169 (2007).
Romero, R. et al. The role of inflammation and infection in preterm birth. Semin. Reprod. Med. 25, 21–39 (2007).
Gombart, A. F., O'Kelly, J., Saito, T. & Koeffler, H. P. Regulation of the CAMP gene by 1,25(OH)2D3 in various tissues. J. Steroid Biochem. Mol. Biol. 103, 552–557 (2007).
Yim, S., Dhawan, P., Ragunath, C., Christakos, S. & Diamond, G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3). J. Cyst. Fibros. 6, 403–410 (2007).
Hansdottir, S. et al. Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J. Immunol. 181, 7090–7099 (2008).
Schauber, J., Dorschner, R. A., Yamasaki, K., Brouha, B. & Gallo, R. L. Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli. Immunology 118, 509–519 (2006).
Lagishetty, V. et al. 1alpha-hydroxylase and innate immune responses to 25-hydroxyvitamin D in colonic cell lines. J. Steroid Biochem. Mol. Biol. 121, 228–233 (2010).
Bell, N. H., Stern, P. H., Pantzer, E., Sinha, T. K. & DeLuca, H. F. Evidence that increased circulating 1 alpha, 25-dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J. Clin. Invest. 64, 218–225 (1979).
Papapoulos, S. E. et al. 1, 25-dihydroxycholecalciferol in the pathogenesis of the hypercalcaemia of sarcoidosis. Lancet 1, 627–630 (1979).
Barbour, G. L., Coburn, J. W., Slatopolsky, E., Norman, A. W. & Horst, R. L. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N. Engl. J. Med. 305, 440–443 (1981).
Adams, J. S., Sharma, O. P., Gacad, M. A. & Singer, F. R. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J. Clin. Invest. 72, 1856–1860 (1983).
Adams, J. S. & Gacad, M. A. Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J. Exp. Med. 161, 755–765 (1985).
Bosch, X. Hypercalcemia due to endogenous overproduction of 1,25-dihydroxyvitamin D in Crohn's disease. Gastroenterology 114, 1061–1065 (1998).
Karakelides, H. et al. Vitamin D-mediated hypercalcemia in slack skin disease: evidence for involvement of extrarenal 25-hydroxyvitamin D 1alpha-hydroxylase. J. Bone Miner. Res. 21, 1496–1499 (2006).
Hewison, M. et al. Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages. J. Bone Miner. Res. 18, 579–582 (2003).
Abreu, M. T. et al. Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut 53, 1129–1136 (2004).
Kallas, M., Green, F., Hewison, M., White, C. & Kline, G. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J. Clin. Endocrinol. Metab. 95, 3111–3117 (2010).
Evans, K. N. et al. Increased expression of 25-hydroxyvitamin D-1alpha-hydroxylase in dysgerminomas: a novel form of humoral hypercalcemia of malignancy. Am. J. Pathol. 165, 807–813 (2004).
Chan, T. Y. Vitamin D deficiency and susceptibility to tuberculosis. Calcif. Tissue Int. 66, 476–478 (2000).
Wejse, C. et al. Serum 25-hydroxyvitamin D in a West African population of tuberculosis patients and unmatched healthy controls. Am. J. Clin. Nutr. 86, 1376–1383 (2007).
Williams, B., Williams, A. J. & Anderson, S. T. Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr. Infect. Dis. J. 27, 941–942 (2008).
Ustianowski, A., Shaffer, R., Collin, S., Wilkinson, R. J. & Davidson, R. N. Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J. Infect. 50, 432–437 (2005).
Chocano-Bedoya, P. & Ronnenberg, A. G. Vitamin D and tuberculosis. Nutr. Rev. 67, 289–293 (2009).
Kamboh, M. I. & Ferrell, R. E. Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations. Hum. Genet. 72, 281–293 (1986).
Martineau, A. R. et al. Association between Gc genotype and susceptibility to TB is dependent on vitamin D status. Eur. Respir. J. 35, 1106–1112 (2010).
Wang, T. J. et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376, 180–188 (2010).
Chun, R. F. et al. Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J. Clin. Endocrinol. Metab. 95, 3368–3376 (2010).
Martineau, A. R., Honecker, F. U., Wilkinson, R. J. & Griffiths, C. J. Vitamin D in the treatment of pulmonary tuberculosis. J. Steroid Biochem. Mol. Biol. 103, 793–798 (2007).
Martineau, A. R. et al. A single dose of vitamin D enhances immunity to mycobacteria. Am. J. Respir. Crit. Care Med. 176, 208–213 (2007).
Nursyam, E. W., Amin, Z. & Rumende, C. M. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med. Indones. 38, 3–5 (2006).
Wejse, C. et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 179, 843–850 (2009).
Janssens, W. et al. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax 65, 215–220 (2010).
Cannell, J. J. et al. Epidemic influenza and vitamin D. Epidemiol. Infect. 134, 1129–1140 (2006).
Aloia, J. F. & Li-Ng, M. Re: epidemic influenza and vitamin D. Epidemiol. Infect. 135, 1095–1096 (2007).
Bergman, P., Walter-Jallow, L., Broliden, K., Agerberth, B. & Söderlund, J. The antimicrobial peptide LL-37 inhibits HIV-1 replication. Curr. HIV Res. 5, 410–415 (2007).
Gombart, A. F. et al. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clin. Infect. Dis. 48, 418–424 (2009).
Jeng, L. et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J. Transl. Med. 7, 28 (2009).
Vagianos, K., Bector, S., McConnell, J. & Bernstein, C. N. Nutrition assessment of patients with inflammatory bowel disease. JPEN J. Parenter. Enteral. Nutr. 31, 311–319 (2007).
Pappa, H. M. et al. Vitamin D status in children and young adults with inflammatory bowel disease. Pediatrics 118, 1950–1961 (2006).
Pappa, H. M., Grand, R. J. & Gordon, C. M. Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease. Inflamm. Bowel Dis. 12, 1162–1174 (2006).
Kong, J. et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G208–G216 (2008).
Froicu, M. & Cantorna, M. T. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol. 8, 5 (2007).
Froicu, M. et al. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol. Endocrinol. 17, 2386–2392 (2003).
Liu, N. et al. Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation. Endocrinology 149, 4799–4808 (2008).
Lagishetty, V. et al. Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis. Endocrinology 151, 2423–2432 (2010).
Cantorna, M. T. Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog. Biophys. Mol. Biol. 92, 60–64 (2006).
Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat. Immunol. 4, 269–273 (2003).
Packey, C. D. & Sartor, R. B. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr. Opin. Infect. Dis. 22, 292–301 (2009).
Gersemann, M., Wehkamp, J., Fellermann, K. & Stange, E. F. Crohn's disease—defect in innate defence. World J. Gastroenterol. 14, 5499–5503 (2008).
Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).
The author declares no competing financial interests.
About this article
Cite this article
Hewison, M. Antibacterial effects of vitamin D. Nat Rev Endocrinol 7, 337–345 (2011). https://doi.org/10.1038/nrendo.2010.226
Evaluation of modifiable risk factors for peritoneal dialysis-related peritonitis: a single-center retrospective cohort study
Renal Replacement Therapy (2021)
European Journal of Clinical Nutrition (2021)
European Journal of Orthopaedic Surgery & Traumatology (2021)
The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19
Journal of Translational Medicine (2020)
Efficacy of high-dose versus low-dose vitamin D supplementation on serum levels of inflammatory factors and mortality rate in severe traumatic brain injury patients: study protocol for a randomized placebo-controlled trial