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Vitamin D Regulation of Immune Function: Implications for Bone Loss During Inflammation

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Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Although the best known actions of vitamin D involve its regulation of bone mineral homeostasis, actions critical for a healthy skeleton, vitamin D exerts its influence on many physiologic processes. One of these processes is the immune system. Both the adaptive and innate immune systems are impacted by the active metabolite of vitamin D, 1,25(OH)2D3. In turn, the immune system is now recognized as having a major impact on the skeleton. In this review, I will examine the regulation by 1,25(OH)2D3 of immune function, then examine the evidence for such regulation as potential means of ameliorating the bone loss that accompanies the inflammatory state.

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References

  1. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007;179:1634–47.

    PubMed  CAS  Google Scholar 

  2. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol. 2007;8:285–93.

    Article  PubMed  CAS  Google Scholar 

  3. Ren S, Nguyen L, Wu S, Encinas C, Adams JS, Hewison M. Alternative splicing of vitamin D-24-hydroxylase: a novel mechanism for the regulation of extrarenal 1,25-dihydroxyvitamin D synthesis. J Biol Chem. 2005;280:20604–11.

    Article  PubMed  CAS  Google Scholar 

  4. Vidal M, Ramana CV, Dusso AS. Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription. Mol Cell Biol. 2002;22:2777–87.

    Article  PubMed  CAS  Google Scholar 

  5. Bikle DD. Extra renal synthesis of 1,25-dihydroxyvitamin D and its health implications. In: Holick MFE, editor. Vitamin D: physiology, molecular biology, and clinical applications. Humana Press; 1999.

  6. Lehmann B, Querings K, Reichrath J. Vitamin D and skin: new aspects for dermatology. Exp Dermatol. 2004;13(Suppl 4):11–5.

    Article  PubMed  CAS  Google Scholar 

  7. Loser K, Mehling A, Loeser S, Apelt J, Kuhn A, Grabbe S, et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006;12:1372–9.

    Article  PubMed  CAS  Google Scholar 

  8. Zasloff M. Sunlight, vitamin D, and the innate immune defenses of the human skin. J Invest Dermatol. 2005;125:16–7.

    Article  Google Scholar 

  9. Pryke AM, Duggan C, White CP, Posen S, Mason RS. Tumor necrosis factor-alpha induces vitamin D-1-hydroxylase activity in normal human alveolar macrophages. J Cell Physiol. 1990;142:652–6.

    Article  PubMed  CAS  Google Scholar 

  10. Gyetko MR, Hsu CH, Wilkinson CC, Patel S, Young E. Monocyte 1 alpha-hydroxylase regulation: induction by inflammatory cytokines and suppression by dexamethasone and uremia toxin. J Leukoc Biol. 1993;54:17–22.

    PubMed  CAS  Google Scholar 

  11. Stoffels K, Overbergh L, Giulietti A, Verlinden L, Bouillon R, Mathieu C. Immune regulation of 25-hydroxyvitamin-D3-1alpha-hydroxylase in human monocytes. J Bone Miner Res. 2006;21:37–47.

    Article  PubMed  CAS  Google Scholar 

  12. Bikle DD, Pillai S, Gee E, Hincenbergs M. Tumor necrosis factor-alpha regulation of 1,25-dihydroxyvitamin D production by human keratinocytes. Endocrinology. 1991;129:33–8.

    Article  PubMed  CAS  Google Scholar 

  13. Bikle DD, Pillai S, Gee E, Hincenbergs M. Regulation of 1,25-dihydroxyvitamin D production in human keratinocytes by interferon-gamma. Endocrinology. 1989;124:655–60.

    Article  PubMed  CAS  Google Scholar 

  14. Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW. Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol. 2008;181:7090–9.

    PubMed  CAS  Google Scholar 

  15. van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 2005;97:93–101.

    Article  PubMed  CAS  Google Scholar 

  16. Daniel C, Sartory NA, Zahn N, Radeke HH, Stein JM. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J Pharmacol Exp Ther. 2008;324:23–33.

    Article  PubMed  CAS  Google Scholar 

  17. Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1 alpha, 25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol. 2001;167:1945–53.

    PubMed  CAS  Google Scholar 

  18. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.

    Article  PubMed  CAS  Google Scholar 

  19. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29:726–76.

    Article  PubMed  CAS  Google Scholar 

  20. Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract. 2008;4:404–12.

    Article  CAS  Google Scholar 

  21. Adamopoulos IE, Bowman EP. Immune regulation of bone loss by Th17 cells. Arthritis Res Ther. 2008;10:225.

    Article  PubMed  CAS  Google Scholar 

  22. Mathieu C, Van Etten E, Gysemans C, Decallonne B, Kato S, Laureys J, et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J Bone Miner Res. 2001;16:2057–65.

    Article  PubMed  CAS  Google Scholar 

  23. O’Kelly J, Hisatake J, Hisatake Y, Bishop J, Norman A, Koeffler HP. Normal myelopoiesis but abnormal T lymphocyte responses in vitamin D receptor knockout mice. J Clin Invest. 2002;109:1091–9.

    PubMed  Google Scholar 

  24. Josien R, Li HL, Ingulli E, Sarma S, Wong BR, Vologodskaia M, et al. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J Exp Med. 2000;191:495–502.

    Article  PubMed  CAS  Google Scholar 

  25. Baroni E, Biffi M, Benigni F, Monno A, Carlucci D, Carmeliet G, et al. VDR-dependent regulation of mast cell maturation mediated by 1,25-dihydroxyvitamin D3. J Leukoc Biol. 2007;81:250–62.

    Article  PubMed  CAS  Google Scholar 

  26. Froicu M, Weaver V, Wynn TA, McDowell MA, Welsh JE, Cantorna MT. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol. 2003;17:2386–92.

    Article  PubMed  CAS  Google Scholar 

  27. Gysemans C, van Etten E, Overbergh L, Giulietti A, Eelen G, Waer M, et al. Unaltered diabetes presentation in NOD mice lacking the vitamin D receptor. Diabetes. 2008;57:269–75.

    Article  PubMed  CAS  Google Scholar 

  28. Topilski I, Flaishon L, Naveh Y, Harmelin A, Levo Y, Shachar I. The anti-inflammatory effects of 1,25-dihydroxyvitamin D3 on Th2 cells in vivo are due in part to the control of integrin-mediated T lymphocyte homing. Eur J Immunol. 2004;34:1068–76.

    Article  PubMed  CAS  Google Scholar 

  29. Wittke A, Weaver V, Mahon BD, August A, Cantorna MT. Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J Immunol. 2004;173:3432–6.

    PubMed  CAS  Google Scholar 

  30. Wittke A, Chang A, Froicu M, Harandi OF, Weaver V, August A, et al. Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation. Arch Biochem Biophys. 2007;460:306–13.

    Article  PubMed  CAS  Google Scholar 

  31. Adorini L. Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cell Immunol. 2005;233:115–24.

    Article  PubMed  CAS  Google Scholar 

  32. Ehrchen J, Helming L, Varga G, Pasche B, Loser K, Gunzer M, et al. Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major. FASEB J. 2007;21:3208–18.

    Article  PubMed  CAS  Google Scholar 

  33. Rajapakse R, Mousli M, Pfaff AW, Uring-Lambert B, Marcellin L, Bronner C, et al. 1,25-Dihydroxyvitamin D3 induces splenocyte apoptosis and enhances BALB/c mice sensitivity to toxoplasmosis. J Steroid Biochem Mol Biol. 2005;96:179–85.

    Article  PubMed  CAS  Google Scholar 

  34. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–80.

    PubMed  CAS  Google Scholar 

  35. Liu PT, Krutzik SR, Modlin RL. Therapeutic implications of the TLR and VDR partnership. Trends Mol Med. 2007;13:117–24.

    Article  PubMed  CAS  Google Scholar 

  36. Schauber J, Gallo RL. The vitamin D pathway: a new target for control of the skin’s immune response? Exp Dermatol. 2008;17:633–9.

    Article  PubMed  CAS  Google Scholar 

  37. Gombart AF, Borregaard N, Koeffler HP. 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. 2005;19:1067–77.

    Article  PubMed  CAS  Google Scholar 

  38. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173:2909–12.

    PubMed  CAS  Google Scholar 

  39. Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 2007;117:803–11.

    Article  PubMed  CAS  Google Scholar 

  40. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–3.

    Article  PubMed  CAS  Google Scholar 

  41. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–60.

    Article  PubMed  CAS  Google Scholar 

  42. Howell MD, Gallo RL, Boguniewicz M, Jones JF, Wong C, Streib JE, et al. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity. 2006;24:341–8.

    Article  PubMed  CAS  Google Scholar 

  43. Ustianowski A, Shaffer R, Collin S, Wilkinson RJ, Davidson RN. Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J Infect. 2005;50:432–7.

    Article  PubMed  CAS  Google Scholar 

  44. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O’Riordan J, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology. 1986;57:159–63.

    PubMed  CAS  Google Scholar 

  45. Liu PT, Stenger S, Tang DH, Modlin RL. Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol. 2007;179:2060–3.

    PubMed  CAS  Google Scholar 

  46. Sly LM, Lopez M, Nauseef WM, Reiner NE. 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. 2001;276:35482–93.

    Article  PubMed  CAS  Google Scholar 

  47. Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science. 1999;285:732–6.

    Article  PubMed  CAS  Google Scholar 

  48. Schauber J, Oda Y, Buchau AS, Yun QC, Steinmeyer A, Zugel U, et al. Histone Acetylation in Keratinocytes Enables Control of the Expression of Cathelicidin and CD14 by 1,25-Dihydroxyvitamin D(3). J Invest Dermatol. 2008;128:816–24.

    Article  PubMed  CAS  Google Scholar 

  49. Leibbrandt A, Penninger JM. RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci. 2008;1143:123–50.

    Article  PubMed  CAS  Google Scholar 

  50. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397:315–23.

    Article  PubMed  CAS  Google Scholar 

  51. Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev. 2007;7:292–304.

    Article  CAS  Google Scholar 

  52. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203:2673–82.

    Article  PubMed  CAS  Google Scholar 

  53. Palmqvist P, Lundberg P, Persson E, Johansson A, Lundgren I, Lie A, et al. Inhibition of hormone and cytokine-stimulated osteoclastogenesis and bone resorption by interleukin-4 and interleukin-13 is associated with increased osteoprotegerin and decreased RANKL and RANK in a STAT6-dependent pathway. J Biol Chem. 2006;281:2414–29.

    Article  PubMed  CAS  Google Scholar 

  54. Ruocco MG, Maeda S, Park JM, Lawrence T, Hsu LC, Cao Y, et al. I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. The Journal of experimental medicine. 2005;201:1677–87.

    Article  PubMed  CAS  Google Scholar 

  55. Evans KE, Fox SW. Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus. BMC Cell Biol. 2007;8:4.

    Article  PubMed  CAS  Google Scholar 

  56. van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS. CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 2004;50:2775–85.

    Article  PubMed  Google Scholar 

  57. Bikle DD. Nonclassical actions of vitamin D. J Endocrinol Metab. 2009;94:26–34.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants RO1 AR050023 and AR051930 from the National Institutes of Health, a Merit Review from the Department of Veterans Affairs, and grant 07A140 from the American Institute of Cancer Research.

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  1. Veterans Affairs Medical Center (111N), 4150 Clement St, San Francisco, CA, 94121, USA

    Daniel D. Bikle

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Bikle, D.D. Vitamin D Regulation of Immune Function: Implications for Bone Loss During Inflammation. Clinic Rev Bone Miner Metab 7, 301–309 (2009). https://doi.org/10.1007/s12018-009-9056-4

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