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Mechanisms of Disease: vitamin D and inflammatory bowel disease

Nature Clinical Practice Gastroenterology & Hepatology volume 2, pages 308–315 (2005)Cite this article

Abstract

Until recently, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)—the active form of vitamin D—was thought to function primarily as a regulator of calcium and phosphate metabolism. More diverse functionality was indicated by the discovery of the vitamin D receptor in tissues that are not involved in calcium and phosphate homeostasis. Detection of the vitamin D receptor in monocytes and activated T cells has sparked interest in the immunomodulatory properties of vitamin D. Here, we review the role of vitamin D in regulation of the immune system, and evidence for its involvement in the pathogenesis of inflammatory bowel disease.

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Figure 1: Vitamin D metabolism and functions.
Figure 2: Immunomodulatory actions of vitamin D.
Figure 3: Prevalence of inflammatory bowel disease from selected registries around the globe.

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References

  1. Holick MF (1994) McCollum Award Lecture, 1994: vitamin D—new horizons for the 21st century. Am J Clin Nutr 60: 619–630

    Article  CAS  Google Scholar 

  2. Haussler MR et al. (1998) The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 13: 325–349

    Article  CAS  Google Scholar 

  3. Sutton AL and MacDonald PN (2003) Vitamin D: more than a “bone-a-fide” hormone. Mol Endocrinol 17: 777–791

    Article  CAS  Google Scholar 

  4. Zittermann A (2003) Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 89: 552–572

    Article  CAS  Google Scholar 

  5. Li YC et al. (2002) 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110: 229–238

    Article  CAS  Google Scholar 

  6. Endo I et al. (2003) Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology 144: 5138–5144

    Article  CAS  Google Scholar 

  7. Zinser G et al. (2002) Vitamin D(3) receptor ablation alters mammary gland morphogenesis. Development 129: 3067–3076

    CAS  PubMed  Google Scholar 

  8. Nagpal S et al. Non-calcemic action of vitamin D receptor ligands. Endocrine Rev, in press

  9. Holick MF (2003) Vitamin D: A millenium perspective. J Cell Biochem 88: 296–307

    Article  CAS  Google Scholar 

  10. Bhalla AK et al. (1983) Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab 57: 1308–1310

    Article  CAS  Google Scholar 

  11. Provvedini DM et al. (1983) 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 221: 1181–1183

    Article  CAS  Google Scholar 

  12. Manolagas SC et al. (1986) The antiproliferative effect of calcitriol on human peripheral blood mononuclear cells. J Clin Endocrinol Metab 63: 394–400

    Article  CAS  Google Scholar 

  13. Brennan A et al. (1987) Dendritic cells from human tissues express receptors for the immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol. Immunology 61: 457–461

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Veldman CM et al. (2000) Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 374: 334–338

    Article  CAS  Google Scholar 

  15. Rigby WF et al. (1984) Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest 74: 1451–1455

    Article  CAS  Google Scholar 

  16. Bhalla AK et al. (1984) 1,25-Dihydroxyvitamin D3 inhibits antigen-induced T cell activation. J Immunol 133: 1748–1754

    CAS  PubMed  Google Scholar 

  17. Stio M et al. (2001) Suppressive effect of 1,25-dihydroxyvitamin D3 and its analogues EB 1089 and KH 1060 on T lymphocyte proliferation in active ulcerative colitis. Biochem Pharmacol 61: 365–371

    Article  CAS  Google Scholar 

  18. Stio M et al. (2002) Synergistic inhibitory effect of cyclosporin A and vitamin D derivatives on T-lymphocyte proliferation in active ulcerative colitis. Am J Gastroenterol 97: 679–689

    Article  CAS  Google Scholar 

  19. Rigby WF et al. (1987) Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA. J Clin Invest 79: 1659–1664

    Article  CAS  Google Scholar 

  20. Lemire JM (1992) Immunomodulatory role of 1,25-dihydroxyvitamin D3. J Cell Biochem 49: 26–31

    Article  CAS  Google Scholar 

  21. Alroy I et al. (1995) Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol 15: 5789–5799

    Article  CAS  Google Scholar 

  22. Cippitelli M and Santoni A (1998) Vitamin D3: a transcriptional modulator of the interferon-gamma gene. Eur J Immunol 28: 3017–3030

    Article  CAS  Google Scholar 

  23. Boonstra A et al. (2001) 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 167: 4974–4980

    Article  CAS  Google Scholar 

  24. Mahon BD et al. (2003) The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem 89: 922–932

    Article  CAS  Google Scholar 

  25. Nashold FE et al. (2001) Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis. J Neuroimmunol 119: 16–29

    Article  CAS  Google Scholar 

  26. Mattner F et al. (2000) Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D(3). Eur J Immunol 30: 498–508

    Article  CAS  Google Scholar 

  27. D'Ambrosio D et al. (1998) Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest 101: 252–262

    Article  CAS  Google Scholar 

  28. Penna G and Adorini L (2000) 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164: 2405–2411

    Article  CAS  Google Scholar 

  29. Piemonti L et al. (2000) Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 164: 4443–4551

    Article  CAS  Google Scholar 

  30. Berer A et al. (2000) 1,25-Dihydroxyvitamin D(3) inhibits dendritic cell differentiation and maturation in vitro. Exp Hematol 28: 575–583

    Article  CAS  Google Scholar 

  31. Canning MO et al. (2001) 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur J Endocrinol 145: 351–357

    Article  CAS  Google Scholar 

  32. Gregori S et al. (2001) Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol 167: 1945–1953

    Article  CAS  Google Scholar 

  33. Barrat FJ et al. (2002) In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 195: 603–616

    Article  CAS  Google Scholar 

  34. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347: 417–429

    Article  CAS  Google Scholar 

  35. Loftus EV Jr and Sandborn WJ (2002) Epidemiology of inflammatory bowel disease. Gastroenterol Clin North Am 31: 1–20

    Article  Google Scholar 

  36. Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 126: 1504–1517

    Article  Google Scholar 

  37. Sellu DP (1986) Seasonal variation in onset of exacerbations of ulcerative proctocolitis. J R Coll Surg Edinb 31: 158–160

    CAS  PubMed  Google Scholar 

  38. Moum B et al. (1996) Seasonal variations in the onset of ulcerative colitis. Gut 38: 376–378

    Article  CAS  Google Scholar 

  39. Zeng L and Anderson FH (1996) Seasonal change in the exacerbations of Crohn's disease. Scand J Gastroenterol 31: 79–82

    Article  CAS  Google Scholar 

  40. Webb AR et al. (1988) Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 67: 373–378

    Article  CAS  Google Scholar 

  41. Vogelsang H et al. (1989) Bone disease in vitamin D-deficient patients with Crohn's disease. Dig Dis Sci 34: 1094–1099

    Article  CAS  Google Scholar 

  42. Holick MF (2002) Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. Curr Opin Endocrinol Diabetes 9: 87–98

    Article  CAS  Google Scholar 

  43. Probert CS et al. (1990) Inflammatory bowel disease in the rural Indian subcontinent: a survey of patients attending mission hospitals. Digestion 47: 42–46

    Article  CAS  Google Scholar 

  44. Probert CS et al. (1992) Epidemiological study of ulcerative proctocolitis in Indian migrants and the indigenous population of Leicestershire. Gut 33: 687–693

    Article  CAS  Google Scholar 

  45. Carr I and Mayberry JF (1999) The effects of migration on ulcerative colitis: a three-year prospective study among Europeans and first- and second-generation South Asians in Leicester (1991-1994). Am J Gastroenterol 94: 2918–2922

    CAS  PubMed  Google Scholar 

  46. Driscoll RH Jr et al. (1982) Vitamin D deficiency and bone disease in patients with Crohn's disease. Gastroenterology 83: 1252–1258

    PubMed  Google Scholar 

  47. Harries AD et al. (1985) Vitamin D status in Crohn's disease: association with nutrition and disease activity. Gut 26: 1197–1203

    Article  CAS  Google Scholar 

  48. Andreassen H et al. (1998) Regulators of calcium homeostasis and bone mineral density in patients with Crohn's disease. Scand J Gastroenterol 33: 1087–1093

    Article  CAS  Google Scholar 

  49. Abitbol V et al. (1995) Metabolic bone assessment in patients with inflammatory bowel disease. Gastroenterology 108: 417–422

    Article  CAS  Google Scholar 

  50. Bernstein CN et al. (1995) Decreased bone density in inflammatory bowel disease is related to corticosteroid use and not disease diagnosis. J Bone Miner Res 10: 250–256

    Article  CAS  Google Scholar 

  51. Abreu MT et al. (2004) 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

    Article  CAS  Google Scholar 

  52. Bernstein CN et al. (2003) AGA technical review on osteoporosis in gastrointestinal diseases. Gastroenterology 124: 795–841

    Article  Google Scholar 

  53. Schoon EJ et al. (2000) Bone mineral density in patients with recently diagnosed inflammatory bowel disease. Gastroenterology 119: 1203–1208

    Article  CAS  Google Scholar 

  54. Lee SH et al. (2000) Decreased trabecular bone mineral density in newly diagnosed inflammatory bowel disease patients in Korea. J Gastroenterol Hepatol 15: 512–518

    Article  CAS  Google Scholar 

  55. Lamb EJ et al. (2002) Metabolic bone disease is present at diagnosis in patients with inflammatory bowel disease. Aliment Pharmacol Ther 16: 1895–902

    Article  CAS  Google Scholar 

  56. Malabanan A et al. (1998) Redefining vitamin D insufficiency. Lancet 351: 805–806

    Article  CAS  Google Scholar 

  57. Chapuy MC et al. (1997) Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 7: 439–443

    Article  CAS  Google Scholar 

  58. Kuhn R et al. (1991) Generation and analysis of interleukin-4 deficient mice. Science 254: 707–710

    Article  CAS  Google Scholar 

  59. Kuhn R et al. (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75: 263–274

    Article  CAS  Google Scholar 

  60. MacDonald TT (1994) Gastrointestinal inflammation. Inflammatory bowel disease in knockout mice. Curr Biol 4: 261–263

    Article  CAS  Google Scholar 

  61. Cantorna MT et al. (2000) 1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J Nutr 130: 2648–2652

    Article  CAS  Google Scholar 

  62. Aranda R et al. (1997) Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients. J Immunol 158: 3464–3473

    CAS  PubMed  Google Scholar 

  63. Morrissey PJ et al. (1993) CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med 178: 237–244

    Article  CAS  Google Scholar 

  64. Froicu M et al. (2003) A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol 17: 2386–2392

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. attending physician at the Department of Gastroenterology, Tan Tock Seng Hospital, Singapore

    Wee-Chian Lim

  2. Professor of Medicine and Chief Department of Medicine, Section of Gastroenterology and Nutrition, University of Chicago, Chicago, IL, USA

    Stephen B Hanauer

  3. Associate Professor of Medicine, in the Department of Medicine, Section of Gastroenterology and Nutrition, University of Chicago, Chicago, IL, USA

    Yan Chun Li

Authors
  1. Wee-Chian Lim
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  2. Stephen B Hanauer
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  3. Yan Chun Li
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Corresponding author

Correspondence to Stephen B Hanauer.

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Glossary

CD28

A T-cell surface molecule and the CD80/CD86 receptor; binding of CD80/CD86 to CD28 is involved in T-cell activation and the initiation and maintenance of chronic inflammation

CD154 (CD40L)

A membrane glycoprotein expressed on T cells; interaction of CD40 with CD154 is important in T-cell activation, T-cell–B-cell crosstalk, B-cell proliferation and differentiation, and memory cell formation

CD80

A cell-surface molecule expressed by monocytes, macrophages, dendritic cells and activated B cells; it binds CD28 and CD152 (important for T-cell co-stimulation and activation, T-cell–B-cell crosstalk, and antibody production)

CD86

A cell-surface molecule expressed at low levels on activated B cells, monocytes, and macrophages, and at high levels on dendritic cells; it binds CD28 and CD152 (important for T-cell co-stimulation and activation, T-cell–B-cell crosstalk, and antibody production)

CD40

A membrane glycoprotein expressed on dendritic cells, monocytes, B cells, and T cells; important in inflammatory pathways (IL-12 production, polarization towards the Th1 type, CD8+ T-cell proliferation, NK cell activation) and B-cell functions

MYCOPHENOLATE MOFETIL

An immunosuppressive drug approved for use in certain organ transplant patients to prevent organ rejection

LEVEL B EVIDENCE

Nonrandomized clinical trials, nonquantitative systematic reviews, clinical cohort and case-controlled studies, high-quality historical uncontrolled studies, and epidemiologic studies

OSTEOMALACIA

Softening or decreased mineralization of the bones caused by a vitamin D deficiency or problems with vitamin D metabolism

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Lim, WC., Hanauer, S. & Li, Y. Mechanisms of Disease: vitamin D and inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2, 308–315 (2005). https://doi.org/10.1038/ncpgasthep0215

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