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Review Article

Role of vitamin D in cytotoxic T lymphocyte immunity to pathogens and cancer

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Pages 132-145 | Received 01 Jan 2015, Accepted 11 Sep 2015, Published online: 19 Oct 2015

References

  • Green M. Cod liver oil and tuberculosis. BMJ 2011;343:d7505
  • Kock W. The first Nobel Prize for medicine to the Nordic countries (Niels Ryberg Finsen 1903). Hist Sci Med 1982;17:144–7
  • Van Der Lugt L, Rottier PB. Finsen therapy and vitamin D. Acta Derm Venereol 1958;38:264–73
  • Grad R. Cod and the consumptive: a brief history of cod-liver oil in the treatment of pulmonary tuberculosis. Pharm Hist 2004;46:106–20
  • Herrera G. Vitamin D in massive doses as an adjuvant to the sulfones in the treatment of tuberculoid leprosy. Int J Leprosy 1949;17:35–42
  • Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc 2011;86:50–60
  • Baeke F, Takiishi T, Korf H, et al. Vitamin D: modulator of the immune system. Curr Opin Pharmacol 2010;10:482–96
  • Hewison M. Vitamin D and the immune system. J Endocrinol 1992;132:173–5
  • Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc 2012;71:50–61
  • Wacker M, Holick MF. Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients 2013;5:111–48
  • Adams JS, Gacad MA. Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med 1985;161:755–65
  • Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983;72:1856–60
  • Bhalla AK, Amento EP, Clemens TL, et al. 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 1983;57:1308–10
  • Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 1983;221:1181–3
  • Omdahl JL, Morris HA, May BK. Hydroxylase enzymes of the vitamin D pathway: expression, function, and regulation. Ann Rev Nutr 2002;22:139–66
  • Panda DK, Miao D, Tremblay ML, et al. Targeted ablation of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci USA 2001;98:7498–503
  • Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008;8:685–98
  • Helming L, Bose J, Ehrchen J, et al. 1alpha,25-Dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation. Blood 2005;106:4351–8
  • Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004;173:2909–12
  • 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
  • Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311:1770–3
  • Edfeldt K, Liu PT, Chun R, et al. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci USA 2010;107:22593–8
  • Piemonti L, Monti P, Sironi M, et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 2000;164:4443–51
  • Szeles L, Keresztes G, Torocsik D, et al. 1,25-Dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype. J Immunol 2009;182:2074–83
  • Griffin MD, Lutz W, Phan VA, et al. Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 2001;98:6800–5
  • Gauzzi MC, Purificato C, Donato K, et al. Suppressive effect of 1alpha,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment of functional activities and chemotaxis. J Immunol 2005;174:270–6
  • Pedersen AW, Holmstrom K, Jensen SS, et al. Phenotypic and functional markers for 1alpha,25-dihydroxyvitamin D(3)-modified regulatory dendritic cells. Clin Exp Immunol 2009;157:48–59
  • Penna G, Adorini L. 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 2000;164:2405–11
  • Penna G, Amuchastegui S, Giarratana N, et al. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol 2007;178:145–53
  • Ferreira GB, van Etten E, Verstuyf A, et al. 1,25-Dihydroxyvitamin D3 alters murine dendritic cell behaviour in vitro and in vivo. Diabetes Metab Res Rev 2011;27:933–41
  • Sigmundsdottir H, Pan J, Debes GF, et al. DCs metabolize sunlight-induced vitamin D3 to ‘program' T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007;8:285–93
  • Fritsche J, Mondal K, Ehrnsperger A, et al. Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells. Blood 2003;102:3314–16
  • Rigby WF, Waugh M, Graziano RF. Regulation of human monocyte HLA-DR and CD4 antigen expression, and antigen presentation by 1,25-dihydroxyvitamin D3. Blood 1990;76:189–97
  • Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 1995;125:1704S–8S
  • Palmer MT, Lee YK, Maynard CL, et al. Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells. J Biol Chem 2011;286:997–1004
  • Joshi S, Pantalena LC, Liu XK, et al. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 2011;31:3653–69
  • Staeva-Vieira TP, Freedman LP. 1,25-dihydroxyvitamin D3 inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4+ T cells. J Immunol 2002;168:1181–9
  • Boonstra A, Barrat FJ, Crain C, et al. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001;167:4974–80
  • Yu XP, Bellido T, Manolagas SC. Down-regulation of NF-kappa B protein levels in activated human lymphocytes by 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1995;92:10990–4
  • Almerighi C, Sinistro A, Cavazza A, et al. 1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine 2009;45:190–7
  • Kuo YT, Kuo CH, Lam KP, et al. Effects of vitamin D3 on expression of tumor necrosis factor-alpha and chemokines by monocytes. J Food Sci 2010;75:H200–4
  • D'Ambrosio D, Cippitelli M, Cocciolo MG, et al. 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 1998;101:252–62
  • Lyakh LA, Sanford M, Chekol S, et al. TGF-beta and vitamin D3 utilize distinct pathways to suppress IL-12 production and modulate rapid differentiation of human monocytes into CD83+ dendritic cells. J Immunol 2005;174:2061–70
  • Muller K, Diamant M, Bendtzen K. Inhibition of production and function of interleukin-6 by 1,25-dihydroxyvitamin D3. Immunol Lett 1991;28:115–20
  • Baeke F, Korf H, Overbergh L, et al. The vitamin D analog, TX527, promotes a human CD4 + CD25highCD127low regulatory T cell profile and induces a migratory signature specific for homing to sites of inflammation. J Immunol 2011;186:132–42
  • Jeffery LE, Wood AM, Qureshi OS, et al. Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses. J Immunol 2012;189:5155–64
  • Jeffery LE, Burke F, Mura M, et al. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 2009;183:5458–67
  • Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1 alpha,25-Dihydroxyvitamin D3-binding macromolecules in human B lymphocytes: effects on immunoglobulin production. J Immunol 1986;136:2734–40
  • Iho S, Takahashi T, Kura F, et al. The effect of 1,25-dihydroxyvitamin D3 on in vitro immunoglobulin production in human B cells. J Immunol 1986;136:4427–31
  • Lemire JM, Adams JS, Sakai R, Jordan SC. 1 alpha,25-Dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 1984;74:657–61
  • Chen S, Sims GP, Chen XX, et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007;179:1634–47
  • Hewison M. Vitamin D and innate and adaptive immunity. Vitam Horm 2011;86:23–62
  • Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients 2013;5:2502–21
  • Hewison M. An update on vitamin D and human immunity. Clin Endocrinol 2012;76:315–25
  • Hewison M. Vitamin D and immune function: autocrine, paracrine or endocrine? Scand J Clin Lab Invest Suppl 2012;243:92–102
  • Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Rheum Dis Clin NA 2012;38:125–39
  • Kongsbak M, Levring TB, Geisler C, von Essen MR. The vitamin d receptor and T cell function. Front Immunol 2013;4:148
  • Peelen E, Knippenberg S, Muris AH, et al. Effects of vitamin D on the peripheral adaptive immune system: a review. Autoimmun Rev 2011;10:733–43
  • Weick MT. A history of rickets in the United States. Am J Clin Nutr 1967;20:1234–41
  • Holick MF. Vitamin D deficiency in 2010: health benefits of vitamin D and sunlight: a D-bate. Nat Rev Endocrinol 2011;7:73–5
  • Studzinski GP, Moore DC. Sunlight - can it prevent as well as cause cancer? Cancer Res 1995;55:4014–22
  • Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010;376:180–8
  • Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 1997;7:439–43
  • Ginde AA, Liu MC, Camargo Jr CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Arch Int Med 2009;169:626–32
  • Ross AC, Taylor CL, Yaktine AL, Del Valle HB, (eds). Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press (US), 2011
  • Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–30
  • Hollis BW, Wagner CL, Drezner MK, Binkley NC. Circulating vitamin D3 and 25-hydroxyvitamin D in humans: an important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol 2007;103:631–4
  • Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 2009;19:73–8
  • Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998;351:805–6
  • Heaney RP, Dowell MS, Hale CA, Bendich A. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 2003;22:142–6
  • Mansbach JM, Ginde AA, Camargo Jr CA. Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D? Pediatrics 2009;124:1404–10
  • Martineau AR. Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis. Proc Nutr Soc 2012;71:84–9
  • Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 2008;37:113–19
  • Chocano-Bedoya P, Ronnenberg AG. Vitamin D and tuberculosis. Nutr Rev 2009;67:289–93
  • Ustianowski A, Shaffer R, Collin S, et al. Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J Infect 2005;50:432–7
  • Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000;355:618–21
  • Williams B, Williams AJ, Anderson ST. Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr Infect Dis J 2008;27:941–2
  • Gao WW, Wang Y, Zhang XR, et al. Levels of 1,25(OH)2D3 for patients with pulmonary tuberculosis and correlations of 1,25(OH)2D3 with the clinical features of TB. J Thorac Dis 2014;6:760–4
  • Waters WR, Palmer MV, Nonnecke BJ, et al. Mycobacterium bovis infection of vitamin D-deficient NOS2-/- mice. Microb Pathog 2004;36:11–17
  • Lu'o'ng K, Nguyen LT. Role of the vitamin D in leprosy. Am J Med Sci 2012;343:471–82
  • Cardoso CC, Pereira AC, de Sales Marques C, Moraes MO. Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome. Future Microbiol 2011;6:533–49
  • Roy S, Frodsham A, Saha B, et al. Association of vitamin D receptor genotype with leprosy type. J Infectious Dis 1999;179:187–91
  • Sapkota BR, Macdonald M, Berrington WR, et al. Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes. Hum Immunol 2010;71:992–8
  • Chaglassian HT. Calciferol treatment of leprosy; preliminary report of two cases. J Investig Dermatol 1948;10:303–4
  • Coussens AK, Wilkinson RJ, Hanifa Y, et al. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc Natl Acad Sci USA 2012;109:15449–54
  • Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 2011;377:242–50
  • Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A single dose of vitamin D enhances immunity to mycobacteria. Am J Resp Crit Care Med 2007;176:208–13
  • Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. J Resp Crit Care Med 2009;179:843–50
  • Martineau AR, Honecker FU, Wilkinson RJ, Griffiths CJ. Vitamin D in the treatment of pulmonary tuberculosis. J Steroid Biochem Mol Biol 2007;103:793–8
  • Bruce D, Whitcomb JP, August A, et al. Elevated non-specific immunity and normal Listeria clearance in young and old vitamin D receptor knockout mice. Int Immunol 2009;21:113–22
  • Havers F, Smeaton L, Gupte N, et al. 25-Hydroxyvitamin D insufficiency and deficiency is associated with HIV disease progression and virological failure post-antiretroviral therapy initiation in diverse multinational settings. J Infectious Dis 2014;210:244–53
  • Coelho L, Cardoso SW, Luz PM, et al. Vitamin D3 supplementation in HIV infection: effectiveness and associations with antiretroviral therapy. Nutr J 2015;14:81. doi: 10.1186/s12937-015-0072-6
  • Coussens AK, Naude CE, Goliath R, et al. High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans. Proc Natl Acad Sci USA 2015;112:8052–7
  • Lachmann R, Bevan MA, Kim S, et al. A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection. AIDS 2015;29:1127–35
  • Stallings VA, Schall JI, Hediger ML, et al. High-dose vitamin D3 supplementation in children and young adults with HIV: a randomized, placebo-controlled trial. Pediatr Infect Dis J 2015;34:e32–40. doi: 10.1097/INF.0000000000000483
  • Chun RF, Liu NQ, Lee T, et al. Vitamin D supplementation and antibacterial immune responses in adolescents and young adults with HIV/AIDS. J Steroid Biochem Mol Biol 2015;148:290–7
  • Garcia-Alvarez M, Pineda-Tenor D, Jimenez-Sousa MA, et al. Relationship of vitamin D status with advanced liver fibrosis and response to hepatitis C virus therapy: a meta-analysis. Hepatology 2014;60:1541–50
  • Gerova DI, Galunska BT, Ivanova, II, et al. Prevalence of vitamin D deficiency and insufficiency in Bulgarian patients with chronic Hepatitis C viral infection. Scand J Clin Lab Invest 2014;74:665–72
  • Guzman-Fulgencio M, Garcia-Alvarez M, Berenguer J, et al. Vitamin D deficiency is associated with severity of liver disease in HIV/HCV coinfected patients. J Infect 2014;68:176–84
  • Villar LM, Del Campo JA, Ranchal I, et al. Association between vitamin D and hepatitis C virus infection: a meta-analysis. World J Gastroenterol 2013;19:5917–24
  • Tillmann HL. Vitamins? The magic bullet against hepatitis C. Expert Rev Anti Infect Ther 2012;10:1273–7
  • Choi B, Lee ES, Sohn S. Vitamin D3 ameliorates herpes simplex virus-induced Behcet's disease-like inflammation in a mouse model through down-regulation of Toll-like receptors. Clin Exp Rheumatol 2011;29:S13–19
  • Farnik H, Bojunga J, Berger A, et al. Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients. Hepatology 2013;58:1270–6
  • Alagarasu K, Honap T, Mulay AP, et al. Association of vitamin D receptor gene polymorphisms with clinical outcomes of dengue virus infection. Hum Immunol 2012;73:1194–9
  • Loke H, Bethell D, Phuong CX, et al. Susceptibility to dengue hemorrhagic fever in vietnam: evidence of an association with variation in the vitamin d receptor and Fc gamma receptor IIa genes. Am J Trop Med Hyg 2002;67:102–6
  • Sanchez-Valdez E, Delgado-Aradillas M, Torres-Martinez JA, Torres-Benitez JM. Clinical response in patients with dengue fever to oral calcium plus vitamin D administration: study of 5 cases. Proc West Pharmacol Soc 2009;52:14–17
  • Giacomet V, Vigano A, Manfredini V, et al. Cholecalciferol supplementation in HIV-infected youth with vitamin D insufficiency: effects on vitamin D status and T-cell phenotype: a randomized controlled trial. HIV Clin Trials 2013;14:51–60
  • Mills EJ, Wu P, Seely D, Guyatt GH. Vitamin supplementation for prevention of mother-to-child transmission of HIV and pre-term delivery: a systematic review of randomized trial including more than 2800 women. AIDS Res Ther 2005;2:4–7
  • Ginde AA, Mansbach JM, Camargo Jr CA. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Int Med 2009;169:384–90
  • McNally JD, Leis K, Matheson LA, et al. Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol 2009;44:981–8
  • Laaksi I, Ruohola JP, Tuohimaa P, et al. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. Am J Clin Nutr 2007;86:714–17
  • Hansdottir S, Monick MM. Vitamin D effects on lung immunity and respiratory diseases. Vitam Horm 2011;86:217–37
  • Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiol Infect 2007;135:1095–6; author reply 7–8
  • Young Jr GA, Underdahl NR, Carpenter LE. Vitamin D intake and susceptibility of mice to experimental swine influenza virus infection. Proc Soc Exp Biol Med 1949;72:695–7
  • Belderbos ME, Houben ML, Wilbrink B, et al. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics 2011;127:e1513–20
  • Hansdottir S, Monick MM, Lovan N, et al. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol 2010;184:965–74
  • Maxwell CS, Carbone ET, Wood RJ. Better newborn vitamin D status lowers RSV-associated bronchiolitis in infants. Nutr Rev 2012;70:548–52
  • Berry DJ, Hesketh K, Power C, Hypponen E. Vitamin D status has a linear association with seasonal infections and lung function in British adults. Br J Nutr 2011;106:1433–40
  • Hope-Simpson RE. The role of season in the epidemiology of influenza. J Hyg (Lond) 1981;86:35–47
  • Shadrin AS, Marinich IG, Taros LY. Experimental and epidemiological estimation of seasonal and climato-geographical features of non-specific resistance of the organism to influenza. J Hyg Epidemiol Microbiol Immunol 1977;21:155–61
  • Sundaram ME, Coleman LA. Vitamin D and influenza. Adv Nutr 2012;3:517–25
  • Shaman J, Jeon CY, Giovannucci E, Lipsitch M. Shortcomings of vitamin D-based model simulations of seasonal influenza. PLoS One 2011;6:e20743
  • Li-Ng M, Aloia JF, Pollack S, et al. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect 2009;137:1396–404
  • Urashima M, Mezawa H, Noya M, Camargo CA. Effects of vitamin D supplements on influenza A illness during the 2009 H1N1 pandemic: a randomized controlled trial. Food Funct 2014;5:2365–70
  • Yamshchikov AV, Desai NS, Blumberg HM, et al. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract 2009;15:438–49
  • Assa A, Vong L, Pinnell LJ, et al. Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation. J Infect Dis 2014;210:1296–305
  • Christakos S. Vitamin D deficiency: protective against enteric infection? Am J Physiol Gastrointest Liver Physiol 2012;303:G1297–8
  • Ryz NR, Patterson SJ, Zhang Y, et al. Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses. Am J Physiol Gastrointest Liver Physiol 2012;303:G1299–311
  • Kim JH, Park JS, Cho YJ, et al. Low serum 25-hydroxyvitamin D level: an independent risk factor for tuberculosis? Clin Nutr 2013;33:1081–6
  • Srinivasan A, Syal K, Banerjee D, et al. Low plasma levels of cholecalciferol and 13-cis-retinoic acid in tuberculosis: implications in host-based chemotherapy. Nutrition 2013;29:1245–51
  • Teles RM, Graeber TG, Krutzik SR, et al. Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses. Science 2013;339:1448–53
  • Goulart LR, Ferreira FR, Goulart IM. Interaction of TaqI polymorphism at exon 9 of the vitamin D receptor gene with the negative lepromin response may favor the occurrence of leprosy. FEMS Immunol Med Microbiol 2006;48:91–8
  • Behar SM. Antigen-specific CD8(+) T cells and protective immunity to tuberculosis. Adv Exp Med Biol 2013;783:141–63
  • Ehrchen J, Helming L, Varga G, et al. Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major. FASEB J 2007;21:3208–18
  • Whitcomb JP, Deagostino M, Ballentine M, et al. The role of vitamin D and vitamin D receptor in immunity to Leishmania major infection. J Parasitol Res 2012;2012:134645. doi: 10.1155/2012/134645. Epub 2011 Oct 11
  • Curtis MM, Way SS. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology 2009;126:177–85
  • Mougneau E, Bihl F, Glaichenhaus N. Cell biology and immunology of Leishmania. Immunol Rev 2011;240:286–96
  • Kriesel JD, Spruance J. Calcitriol (1,25-dihydroxy-vitamin D3) coadministered with influenza vaccine does not enhance humoral immunity in human volunteers. Vaccine 1999;17:1883–8
  • Science M, Maguire JL, Russell ML, et al. Serum 25-hydroxyvitamin d level and influenza vaccine immunogenicity in children and adolescents. PLoS One 2014;9:e83553
  • Rees JR, Hendricks K, Barry EL, et al. Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial. Clin Infect Dis 2013;57:1384–92
  • Onodera T, Takahashi Y, Yokoi Y, et al. Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection. Proc Natl Acad Sci USA 2012;109:2485–90
  • Cooper C, Thorne A, Canadian HIV Trials Network Ctn Influenza Vaccine Research G. Vitamin D supplementation does not increase immunogenicity of seasonal influenza vaccine in HIV-infected adults. HIV Clin Trials 2011;12:275–6
  • D'Elia RV, Harrison K, Oyston PC, et al. Targeting the “cytokine storm” for therapeutic benefit. Clin Vaccine Immunol 2013;20:319–27
  • Baskin CR, Bielefeldt-Ohmann H, Tumpey TM, et al. Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proc Natl Acad Sci USA 2009;106:3455–60
  • Everitt AR, Clare S, Pertel T, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 2012;484:519–23
  • Kash JC, Tumpey TM, Proll SC, et al. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 2006;443:578–81
  • Lee YT, Kim KH, Ko EJ, et al. New vaccines against influenza virus. Clin Exp Vaccine Res 2014;3:12–28
  • Sun J, Braciale TJ. Role of T cell immunity in recovery from influenza virus infection. Curr Opin Virol 2013;3:425–9
  • Khare D, Godbole NM, Pawar SD, et al. Calcitriol [1, 25[OH]2 D3] pre- and post-treatment suppresses inflammatory response to influenza A (H1N1) infection in human lung A549 epithelial cells. Eur J Nutr 2013;52:1405–15
  • He X, Yan J, Zhu X, et al. Vitamin D inhibits the occurrence of experimental cerebral malaria in mice by suppressing the host inflammatory response. J Immunol 2014;193:1314–23
  • Waisberg M, Vickers BK, Yager SB, et al. Testing in mice the hypothesis that melanin is protective in malaria infections. PLoS One 2012;7:e29493
  • Tse SW, Radtke AJ, Zavala F. Induction and maintenance of protective CD8+ T cells against malaria liver stages: implications for vaccine development. Mem Inst Oswaldo Cruz 2011;106:172–8
  • Van Braeckel-Budimir N, Harty JT. CD8 T-cell-mediated protection against liver-stage malaria: lessons from a mouse model. Frontiers Microbiol 2014;5:272
  • Feldman D, Krishnan AV, Swami S, et al. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 2014;14:342–57
  • Starska K, Glowacka E, Kulig A, et al. Prognostic value of the immunological phenomena and relationship with clinicopathological characteristics of the tumor - the expression of the early CD69+, CD71+ and the late CD25+, CD26+, HLA/DR+ activation markers on T CD4+ and CD8+ lymphocytes in squamous cell laryngeal carcinoma. Part II. Folia Histochem Cytobiol 2011;49:593–603
  • Starska K, Glowacka E, Kulig A, et al. The role of tumor cells in the modification of T lymphocytes activity - the expression of the early CD69+, CD71+ and the late CD25+, CD26+, HLA/DR+ activation markers on T CD4+ and CD8+ cells in squamous cell laryngeal carcinoma. Part I. Folia Histochem Cytobiol 2011;49:579–92
  • Walsh JE, Clark AM, Day TA, et al. Use of alpha,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma. Hum Immunol 2010;71:659–65
  • Young MR, Halpin J, Wang J, et al. 1 alpha,25-dihydroxyvitamin D3 plus gamma-interferon blocks lung tumor production of granulocyte-macrophage colony-stimulating factor and induction of immunosuppressor cells. Cancer Res 1993;53:6006–10
  • Zinkernagel RM, Doherty PC. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol 1979;27:51–77
  • Zinkernagel RM, Doherty PC. The discovery of MHC restriction. Immunol Today 1997;18:14–7
  • Kalia V, Sarkar S, Ahmed R. CD8 T-cell memory differentiation during acute and chronic viral infections. Adv Exp Med Biol 2010;684:79–95
  • Kalia V, Sarkar S, Gourley TS, et al. Differentiation of memory B and T cells. Curr Opin Immunol 2006;18:255–64
  • Williams MA, Bevan MJ. Effector and memory CTL differentiation. Annu Rev Immunol 2007;25:171–92
  • Curtsinger JM, Johnson CM, Mescher MF. CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J Immunol 2003;171:5165–71
  • Curtsinger JM, Mescher MF. Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 2010;22:333–40
  • Curtsinger JM, Schmidt CS, Mondino A, et al. Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J Immunol 1999;162:3256–62
  • Curtsinger JM, Valenzuela JO, Agarwal P, et al. Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol 2005;174:4465–9
  • Kolumam GA, Thomas S, Thompson LJ, et al. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med 2005;202:637–50
  • Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity 2011;35:161–8
  • Yuzefpolskiy Y, Baumann FM, Kalia V, Sarkar S. Early CD8 T-cell memory precursors and terminal effectors exhibit equipotent in vivo degranulation. Cell Mol Immunol 2015;12:400–8
  • Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity 2008;29:848–62
  • Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002;2:251–62
  • Khoo AL, Chai LY, Koenen HJ, et al. Regulation of cytokine responses by seasonality of vitamin D status in healthy individuals. Clin Exp Immunol 2011;164:72–9
  • Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development. Proc Natl Acad Sci USA 2008;105:5207–12
  • von Essen MR, Kongsbak M, Schjerling P, et al. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 2010;11:344–9
  • Ooi JH, McDaniel KL, Weaver V, Cantorna MT. Murine CD8+ T cells but not macrophages express the vitamin D 1alpha-hydroxylase. J Nutr Biochem 2014;25:58–65
  • Yang HF, Zhang ZH, Chang ZQ, et al. Vitamin D deficiency affects the immunity against Mycobacterium tuberculosis infection in mice. Clin Exp Med 2013;13:265–70
  • Lemire JM, Adams JS, Kermani-Arab V, et al. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J Immunol 1985;134:3032–5
  • Vanham G, Ceuppens JL, Bouillon R. T lymphocytes and their CD4 subset are direct targets for the inhibitory effect of calcitriol. Cell Immunol 1989;124:320–33
  • Thien R, Baier K, Pietschmann P, et al. Interactions of 1 alpha,25-dihydroxyvitamin D3 with IL-12 and IL-4 on cytokine expression of human T lymphocytes. J Allergy Clin Immunol 2005;116:683–9
  • Chen J, Bruce D, Cantorna MT. Vitamin D receptor expression controls proliferation of naive CD8+ T cells and development of CD8 mediated gastrointestinal inflammation. BMC Immun 2014;15:6
  • Meehan MA, Kerman RH, Lemire JM. 1,25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell Immunol 1992;140:400–9
  • Lysandropoulos AP, Jaquiery E, Jilek S, et al. Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects. J Neuroimmunol 2011;233:240–4
  • Prabhu Anand S, Selvaraj P, Narayanan PR. Effect of 1,25 dihydroxyvitamin D3 on intracellular IFN-gamma and TNF-alpha positive T cell subsets in pulmonary tuberculosis. Cytokine 2009;45:105–10
  • Willheim M, Thien R, Schrattbauer K, et al. Regulatory effects of 1alpha,25-dihydroxyvitamin D3 on the cytokine production of human peripheral blood lymphocytes. J Clin Endocrinol Metab 1999;84:3739–44
  • Dimeloe S, Richards DF, Urry ZL, et al. 1alpha,25-dihydroxyvitamin D3 promotes CD200 expression by human peripheral and airway-resident T cells. Thorax 2012;67:574–81
  • Baeke F, Korf H, Overbergh L, et al. Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system. J Steroid Biochem Mol Biol 2010;121:221–7
  • Oldstone MB. Lessons learned and concepts formed from study of the pathogenesis of the two negative-strand viruses lymphocytic choriomeningitis and influenza. Proc Natl Acad Sci USA 2013;110:4180–3
  • Zhou X, Ramachandran S, Mann M, Popkin DL. Role of lymphocytic choriomeningitis virus (LCMV) in understanding viral immunology: past, present and future. Viruses 2012;4:2650–69
  • Yuzefpolskiy Y, Baumann FM, Penny LA, et al. Vitamin D Receptor signals regulate effector and memory CD8 T cell responses to infections in mice. J Nutr 2014;144:2073–82
  • Sarkar S, Kalia V, Haining WN, et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J Exp Med 2008;205:625–40
  • Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol 2007;19:408–15
  • Wherry EJ. T cell exhaustion. Nat Immunol 2011;12:492–9
  • Sarkar S, Teichgraber V, Kalia V, et al. Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation. J Immunol 2007;179:6704–14
  • Cantrell DA, Smith KA. Transient expression of interleukin 2 receptors. Consequences for T cell growth. J Exp Med 1983;158:1895–911
  • Cantrell DA, Smith KA. The interleukin-2 T-cell system: a new cell growth model. Science 1984;224:1312–16
  • Kalia V, Sarkar S, Subramaniam S, et al. Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 2010;32:91–103
  • Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 2010;33:153–65
  • Pipkin ME, Sacks JA, Cruz-Guilloty F, et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 2010;32:79–90
  • Feau S, Arens R, Togher S, Schoenberger SP. Autocrine IL-2 is required for secondary population expansion of CD8(+) memory T cells. Nat Immunol 2011;12:908–13
  • Blattman JN, Grayson JM, Wherry EJ, et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat Med 2003;9:540–7
  • Ben-Sasson SZ, Hogg A, Hu-Li J, et al. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J Exp Med 2013;210:491–502
  • Ben-Sasson SZ, Wang K, Cohen J, Paul WE. IL-1beta Strikingly enhances antigen-driven CD4 and CD8 T-cell responses. Cold Spring Harb Symp Quant Biol 2013;78:117–24
  • Joshi NS, Cui W, Chandele A, et al. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 2007;27:281–95
  • Brooks DG, Trifilo MJ, Edelmann KH, et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 2006;12:1301–9
  • Lund JM, Hsing L, Pham TT, Rudensky AY. Coordination of early protective immunity to viral infection by regulatory T cells. Science 2008;320:1220–4
  • Pace L, Tempez A, Arnold-Schrauf C, et al. Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science 2012;338:532–6
  • Suvas S, Kumaraguru U, Pack CD, et al. CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 2003;198:889–901
  • Rutishauser RL, Kaech SM. Generating diversity: transcriptional regulation of effector and memory CD8 T-cell differentiation. Immunol Rev 2010;235:219–33
  • Ichii H, Sakamoto A, Hatano M, et al. Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat Immunol 2002;3:558–63
  • Yang CY, Best JA, Knell J, et al. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat Immunol 2011;12:1221–9
  • Weant AE, Michalek RD, Khan IU, et al. Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8+ T cell contraction. Immunity 2008;28:218–30
  • Huster KM, Busch V, Schiemann M, et al. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Proc Natl Acad Sci USA 2004;101:5610–15
  • Kaech SM, Tan JT, Wherry EJ, et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 2003;4:1191–8
  • Araki K, Ellebedy AH, Ahmed R. TOR in the immune system. Curr Opin Cell Biol 2011;23:707–15
  • Araki K, Turner AP, Shaffer VO, et al. mTOR regulates memory CD8 T-cell differentiation. Nature 2009;460:108–12
  • Khan AA, Penny LA, Yuzefpolskiy Y, et al. MicroRNA-17∼92 regulates effector and memory CD8 T-cell fates by modulating proliferation in response to infections. Blood 2013;121:4473–83
  • Wang J, Zhao Y, Kauss MA, et al. Akt regulates vitamin D3-induced leukemia cell functional differentiation via Raf/MEK/ERK MAPK signaling. Eur J Cell Biol 2009;88:103–15
  • Wang X, Pesakhov S, Weng A, et al. ERK 5/MAPK pathway has a major role in 1alpha,25-(OH)2 vitamin D3-induced terminal differentiation of myeloid leukemia cells. J Steroid Biochem Mol Biol 2014;144:223–7
  • Wang X, Studzinski GP. Raf-1 signaling is required for the later stages of 1,25-dihydroxyvitamin D3-induced differentiation of HL60 cells but is not mediated by the MEK/ERK module. J Cell Physiol 2006;209:253–60
  • Buitrago CG, Ronda AC, de Boland AR, Boland R. MAP kinases p38 and JNK are activated by the steroid hormone 1alpha,25(OH)2-vitamin D3 in the C2C12 muscle cell line. J Cell Biochem 2006;97:698–708
  • Jamshidi F, Zhang J, Harrison JS, Wang X, Studzinski GP. Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1,25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling. Cell Cycle 2008;7:917–24
  • Jiang Y, Fleet JC. Phorbol esters enhance 1alpha,25-dihydroxyvitamin D3-regulated 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) gene expression through ERK-mediated phosphorylation of specific protein 3 (Sp3) in Caco-2 cells. Mol Cell Endocrinol 2012;361:31–9
  • Jiang Y, Fleet JC. Effect of phorbol 12-myristate 13-acetate activated signaling pathways on 1alpha, 25 dihydroxyvitamin D3 regulated human 25-hydroxyvitamin D3 24-hydroxylase gene expression in differentiated Caco-2 cells. J Cell Biochem 2012;113:1599–607
  • Rossi AM, Capiati DA, Picotto G, et al. MAPK inhibition by 1alpha,25(OH)2-Vitamin D3 in breast cancer cells. Evidence on the participation of the VDR and Src. J Steroid Biochem Mol Biol 2004;89–90:287–90
  • Cui M, Zhao Y, Hance KW, et al. Effects of MAPK signaling on 1,25-dihydroxyvitamin D-mediated CYP24 gene expression in the enterocyte-like cell line, Caco-2. J Cell Physiol 2009;219:132–42
  • Kersh EN, Kaech SM, Onami TM, et al. TCR signal transduction in antigen-specific memory CD8 T cells. J Immunol 2003;170:5455–63
  • Buchholz VR, Flossdorf M, Hensel I, et al. Disparate individual fates compose robust CD8+ T cell immunity. Science 2013;340:630–5
  • Gerlach C, Rohr JC, Perie L, et al. Heterogeneous differentiation patterns of individual CD8+ T cells. Science 2013;340:635–9
  • Jensen SS, Madsen MW, Lukas J, et al. Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery. Mol Endocrinol 2001;15:1370–80
  • Verlinden L, Verstuyf A, Convents R, et al. Action of 1,25(OH)2D3 on the cell cycle genes, cyclin D1, p21 and p27 in MCF-7 cells. Mol Cell Endocrinol 1998;142:57–65
  • Lisse TS, Hewison M. Vitamin D: a new player in the world of mTOR signaling. Cell Cycle 2011;10:1888–9
  • Lisse TS, Liu T, Irmler M, et al. Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling. FASEB J 2011;25:937–47
  • Fetahu IS, Hobaus J, Kallay E. Vitamin D and the epigenome. Frontiers Physiol 2014;5:164
  • Weng NP, Araki Y, Subedi K. The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat Rev Immunol 2012;12:306–15
  • Northrop JK, Wells AD, Shen H. Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J Immunol 2008;181:865–8
  • Pearce EL, Shen H. Making sense of inflammation, epigenetics, and memory CD8+ T-cell differentiation in the context of infection. Immunol Rev 2006;211:197–202
  • Youngblood B, Davis CW, Ahmed R. Making memories that last a lifetime: heritable functions of self-renewing memory CD8 T cells. Int Immunol 2010;22:797–803
  • Janssen EM, Droin NM, Lemmens EE, et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 2005;434:88–93
  • Janssen EM, Lemmens EE, Wolfe T, et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003;421:852–6
  • Khanolkar A, Fuller MJ, Zajac AJ. CD4 T cell-dependent CD8 T cell maturation. J Immunol 2004;172:2834–44
  • Schoenberger SP, Toes RE, van der Voort EI, et al. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998;393:480–3
  • Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003;300:337–9
  • Sun JC, Bevan MJ. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 2003;300:339–42
  • Sun JC, Williams MA, Bevan MJ. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat Immunol 2004;5:927–33
  • Asano MS, Ahmed R. CD8 T cell memory in B cell-deficient mice. J Exp Med 1996;183:2165–74
  • Whitmire JK, Asano MS, Kaech SM, et al. Requirement of B cells for generating CD4+ T cell memory. J Immunol 2009;182:1868–76
  • Soderquest K, Walzer T, Zafirova B, et al. Cutting edge: CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses. J Immunol 2011;186:3304–8
  • Stadnisky MD, Xie X, Coats ER, et al. Self MHC class I-licensed NK cells enhance adaptive CD8 T-cell viral immunity. Blood 2011;117:5133–41
  • Kalia V, Penny LA, Yuzefpolskiy Y, et al. Quiescence of memory CD8(+) T cells is mediated by regulatory T cells through inhibitory receptor CTLA-4. Immunity 2015;42:1116–29
  • Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 2012;12:749–61
  • Chun RF, Liu PT, Modlin RL, et al. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Frontiers Physiol 2014;5:151
  • Fernandez-Garcia NI, Palmer HG, Garcia M, et al. 1alpha,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells. Oncogene 2005;24:6533–44
  • Gumireddy K, Ikegaki N, Phillips PC, et al. Effect of 20-epi-1alpha,25-dihydroxyvitamin D3 on the proliferation of human neuroblastoma: role of cell cycle regulators and the Myc-Id2 pathway. Biochem Pharmacol 2003;65:1943–55
  • Neve A, Corrado A, Cantatore FP. Immunomodulatory effects of vitamin D in peripheral blood monocyte-derived macrophages from patients with rheumatoid arthritis. Clin Exp Med 2014;14:275–83
  • Seif AA, Abdelwahed DM. Vitamin D ameliorates hepatic ischemic/reperfusion injury in rats. J Physiol Biochem 2014;70:659–66
  • Verway M, Bouttier M, Wang TT, et al. Vitamin D induces interleukin-1beta expression: paracrine macrophage epithelial signaling controls M. tuberculosis infection. PLoS Pathog 2013;9:e1003407
  • Giulietti A, van Etten E, Overbergh L, et al. Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Res Clin Pract 2007;77:47–57
  • Alroy I, Towers TL, Freedman LP. 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 1995;15:5789–99
  • Hughes PJ, Lee JS, Reiner NE, Brown G. The vitamin D receptor-mediated activation of phosphatidylinositol 3-kinase (PI3Kalpha) plays a role in the 1alpha,25-dihydroxyvitamin D3-stimulated increase in steroid sulphatase activity in myeloid leukaemic cell lines. J Cell Biochem 2008;103:1551–72
  • Tse AK, Wan CK, Shen XL, et al. 1,25-dihydroxyvitamin D3 induces biphasic NF-kappaB responses during HL-60 leukemia cells differentiation through protein induction and PI3K/Akt-dependent phosphorylation/degradation of IkappaB. Exp Cell Res 2007;313:1722–34
  • Datta-Mitra A, Mitra A, Ray R, et al. 1,25-Dihydroxyvitamin D3-3-bromoacetate, a novel vitamin D analog induces immunosuppression through PI3K/Akt/mTOR signaling cascade. Int Immunopharmacol 2013;17:744–51
  • Hoes JN, Van der Goes MC, Jacobs JW, et al. Changes in macrophage inhibitory factor correlate with changes in bone mineral density in glucocorticoid-treated patients with rheumatoid arthritis. Rheumatology 2011;50:1921–4
  • Bao A, Li Y, Tong Y, et al. Tumor-suppressive effects of 1, 25-dihydroxyvitamin D3 in gastric cancer cells. Hepatogastroenterology 2013;60:943–8
  • Zhang Y, Zhang J, Studzinski GP. AKT pathway is activated by 1, 25-dihydroxyvitamin D3 and participates in its anti-apoptotic effect and cell cycle control in differentiating HL60 cells. Cell Cycle 2006;5:447–51
  • Niino M, Fukazawa T, Miyazaki Y, et al. Suppression of IL-10 production by calcitriol in patients with multiple sclerosis. J Neuroimmunol 2014;270:86–94
  • Korf H, Wenes M, Stijlemans B, et al. 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism. Immunobiology 2012;217:1292–300
  • Bischoff-Ferrari HA, Dawson-Hughes B, Stocklin E, et al. Oral supplementation with 25(OH)D3 versus vitamin D3: effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J Bone Min Res 2012;27:160–9
  • Gysemans CA, Cardozo AK, Callewaert H, et al. 1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology 2005;146:1956–64
  • Montoya D, Inkeles MS, Liu PT, et al. IL-32 is a molecular marker of a host defense network in human tuberculosis. Sci Trans Med 2014;6:250ra114
  • Liu NQ, Kaplan AT, Lagishetty V, et al. Vitamin D and the regulation of placental inflammation. J Immunol 2011;186:5968–74
  • Bettoun DJ, Buck 2nd DW, Lu J, et al. A vitamin D receptor-Ser/Thr phosphatase-p70 S6 kinase complex and modulation of its enzymatic activities by the ligand. J Biol Chem 2002;277:24847–50
  • Halicka HD, Zhao H, Li J, et al. Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage-signaling. Aging (Albany NY) 2012;4:952–65
  • Breuer J, Schwab N, Schneider-Hohendorf T, et al. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Ann Neurol 2014;75:739–58
  • Eelen G, Verlinden L, Meyer MB, et al. 1,25-Dihydroxyvitamin D3 and the aging-related forkhead box O and sestrin proteins in osteoblasts. J Steroid Biochem Mol Biol 2013;136:112–19
  • Inoue M, Matsui T, Nishibu A, et al. Regulatory effects of 1alpha,25-dihydroxyvitamin D3 on inflammatory responses in psoriasis. Eur J Dermatol 1998;8:16–20
  • Khoo AL, Chai LY, Koenen HJ, et al. Vitamin D(3) down-regulates proinflammatory cytokine response to Mycobacterium tuberculosis through pattern recognition receptors while inducing protective cathelicidin production. Cytokine 2011;55:294–300
  • Khoo AL, Chai LY, Koenen HJ, et al. 1,25-dihydroxyvitamin D3 modulates cytokine production induced by Candida albicans: impact of seasonal variation of immune responses. J Infect Diseases 2011;203:122–30
  • Morales O, Faulds MH, Lindgren UJ, Haldosen LA. 1Alpha,25-dihydroxyvitamin D3 inhibits GH-induced expression of SOCS-3 and CIS and prolongs growth hormone signaling via the Janus kinase (JAK2)/signal transducers and activators of transcription (STAT5) system in osteoblast-like cells. J Biol Chem 2002;277:34879–84
  • Jiang YJ, Teichert AE, Fong F, et al. 1alpha,25(OH)2-dihydroxyvitamin D3/VDR protects the skin from UVB-induced tumor formation by interacting with the beta-catenin pathway. J Steroid Biochem Mol Biol 2013;136:229–32
  • Bikle DD, Elalieh H, Welsh J, et al. Protective role of vitamin D signaling in skin cancer formation. J Steroid Biochem Mol Biol 2013;136:271–9
  • Palmer HG, Gonzalez-Sancho JM, Espada J, et al. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol 2001;154:369–87
  • Lee CJ, Subeq YM, Lee RP, et al. Calcitriol decreases TGF-beta1 and angiotensin II production and protects against chlorhexide digluconate-induced liver peritoneal fibrosis in rats. Cytokine 2014;65:105–18
  • Wobke TK, von Knethen A, Steinhilber D, Sorg BL. CD69 is a TGF-beta/1alpha,25-dihydroxyvitamin D3 target gene in monocytes. PLoS One 2013;8:e64635
  • Corduk N, Abban G, Yildirim B, Sarioglu-Buke A. The effect of vitamin D on expression of TGF beta1 in ovary. Exp Clin Endocrinol Diabetes 2012;120:490–3
  • Liaskou E, Jeffery LE, Trivedi PJ, et al. Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. Gastroenterology 2014;147:221–32 e7
  • Hoyer-Hansen M, Jaattela M. AMP-activated protein kinase: a universal regulator of autophagy? Autophagy 2007;3:381–3
  • Choi M, Park H, Cho S, Lee M. Vitamin D3 supplementation modulates inflammatory responses from the muscle damage induced by high-intensity exercise in SD rats. Cytokine 2013;63:27–35
  • Daniel C, Radeke HH, Sartory NA, et al. The new low calcemic vitamin D analog 22-ene-25-oxa-vitamin D prominently ameliorates T helper cell type 1-mediated colitis in mice. J Pharmacol Exp Therapeutics 2006;319:622–31
  • Lange CM, Gouttenoire J, Duong FH, et al. Vitamin D receptor and Jak-STAT signaling crosstalk results in calcitriol-mediated increase of hepatocellular response to IFN-alpha. J Immunol 2014;192:6037–44
  • Matsuzaki J, Tsuji T, Zhang Y, et al. 1alpha,25-Dihydroxyvitamin D3 downmodulates the functional differentiation of Th1 cytokine-conditioned bone marrow-derived dendritic cells beneficial for cytotoxic T lymphocyte generation. Cancer Sci 2006;97:139–47
  • 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
  • Stoppelenburg AJ, von Hegedus JH, Huis in't Veld R, et al. Defective control of vitamin D receptor-mediated epithelial STAT1 signalling predisposes to severe respiratory syncytial virus bronchiolitis. J Pathol 2014;232:57–64
  • Muthian G, Raikwar HP, Rajasingh J, Bright JJ. 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res 2006;83:1299–309
  • Halder SK, Sharan C, Al-Hendy A. 1,25-dihydroxyvitamin D3 treatment shrinks uterine leiomyoma tumors in the Eker rat model. Biol Reprod 2012;86:116
  • Gocek E, Wang X, Liu X, et al. MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res 2011;71:6230–9
  • Xu HM, Tepper CG, Jones JB, et al. 1,25-Dihydroxyvitamin D3 protects HL60 cells against apoptosis but down-regulates the expression of the bcl-2 gene. Exp Cell Res 1993;209:367–74
  • Mouratidis PX, Dalgleish AG, Colston KW. Investigation of the mechanisms by which EB1089 abrogates apoptosis induced by 9-cis retinoic acid in pancreatic cancer cells. Pancreas 2006;32:93–100

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