ISRN Nephrology

Volume 2013 (2013), Article ID 898125, 6 pages

http://dx.doi.org/10.5402/2013/898125

Review Article

The Pleiotropic Effect of Vitamin D

Yu-Hsien Lai¹ and Te-Chao Fang1,2,3

¹Division of Nephrology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Chung Yang Road, Hualien 97004, Taiwan

²School of Medicine, Tzu Chi University, Hualien, Taiwan

³Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan

Received 17 June 2013; Accepted 5 August 2013

Academic Editors: T. Doi and C. G. Musso

Copyright © 2013 Yu-Hsien Lai and Te-Chao Fang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The novel roles of vitamin D were discovered and valued in this century. In addition to the maintenance of calcium and phosphorus balance, vitamin D regulates the function of the kidneys, heart, and immune system. Moreover, its anti-inflammatory, antiapoptotic, and antifibrotic roles have gained considerable attention. Vitamin D is also important for the maintenance of homeostasis by regulation of hormone secretion, cell proliferation, and differentiation. This paper will review these pleiotropic functions of vitamin D.

1. Introduction

Since the beginning of the 20th century, scientists have been exploring the functions of vitamin D. The roles of this vitamin in endocrine system and metabolic bone diseases were already well studied by 1970. In this century, the discovery of vitamin D receptor has provided more insight on its additional functions [1]. Vitamin D receptors are present on many organs, such as the pancreas, large and small intestines, muscles, and nervous system [2]. Vitamin D was found to regulate the cell cycle and subsequently influence organ functions by binding to its receptor on the cells of the immune, nervous, and cardiovascular systems [3]. In the kidneys, vitamin D exerts protective effects by inhibiting renal fibrosis, inflammation, and progression of proteinuria.

Vitamin D deficiency is strongly associated with various cardiovascular and metabolic diseases such as hypertension, type 1 diabetes, myocardial infarction, and stroke. Moreover, vitamin D deficiency is related to several autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus. Studies also have shown a negative correlation between serum vitamin D concentration and incidence of colorectal cancer and breast cancer [4]. These phenomena suggest that vitamin D plays protective roles in many diseases. As the importance of vitamin D for endocrine function has gained attention, the pursuit of paracrine and autocrine functions of vitamin D will continue in this century [5].

2. Metabolism of Vitamin D

Vitamin D is a fat-soluble vitamin produced by exposure of the skin to sufficient ultraviolet B radiation and absorption from the gastrointestinal tract. After vitamin D₃ is synthesized, it is transported to the liver where 25-hydroxyvitamin D₃ is formed via hydroxylation by 25-hydroxylase. 25-Hydroxyvitamin D₃ is further converted into the physiologically active vitamin D₃ (1,25-dihydroxyvitamin D₃) in the mitochondria of the proximal convoluted tubules. The active vitamin D₃ and vitamin D-binding protein are then transported to different organs for further metabolism [6]. In patients with chronic kidney disease, the serum level of the active form of vitamin D₃ is decreased because of elevated blood concentration of fibroblast growth factor-23 (FGF-23) and related inflammatory cytokines [7, 8]. Because the level of circulating vitamin D₃ decreases, the levels of 25-hydroxyvitamin D entering other types of cells also reduce relatively [9].

The daily recommended vitamin D intake is 5–15 μg, but the amount of vitamin D from UV irradiation via skin or oral intake is inadequate to meet the demand for most people nowadays [5]. Because the incidence of vitamin D toxicity is rare in healthy adults, increased daily vitamin D intake is suggested [8, 10]. If the daily intake of vitamin D can reach 50 μg, the concentration of serum vitamin D in the blood can increase from 25 nmol/L to 75 nmol/L [11]. Increasing vitamin D intake would be helpful in disease prevention and management [12].

3. Vitamin D Receptor

The gene for vitamin D receptor was discovered in 1988 and has been found to be present in the cells of many tissues, including parathyroid cells, pancreatic cells, macrophages, keratinocytes, special nerve cells, and renal tubular cells. Vitamin D receptor is widely expressed in almost all cells, and vitamin D regulates approximately 3% of the human genes via its endocrine effects [13]. The active form of vitamin D is released in smooth muscle, colon, and immune cells, besides renal cells, via local hydroxylation of 25-hydroxyvitamin D by 1α-hydroxylases [14, 15].

4. Anti-Inflammatory Effect of Vitamin D

One of the functions of vitamin D is to promote the differentiation of monocytes into macrophages, dendritic cells, and lymphocytes. These cells represent the first line of defense of the nonspecific immune system and play an important role in infection control [10]. Many studies have found that the lack of vitamin D or vitamin D receptor causes altered innate and adaptive immune functions. Patients with diseases associated with vitamin D deficiency, such as rickets or chronic kidney disease, are known to have recurrent infections [16, 17]. The effect of vitamin D on immune system can be attributed to the paracrine feedback mechanism, whereby it reduces inflammatory response, affects the differentiation of active CD4⁺ T cells, and enhances the inhibitory function of T cells. The active form of vitamin D also promotes the differentiation of monocytes into mature macrophages by induction of p21 [18]. C/EBPβ (CCAAT-enhancer-binding protein beta) is an important transcriptional factor which provides macrophages with antibacterial, antiviral, and antitumor activities and for the IL-12 synthesis [19]. Vitamin D induces C/EBPβ that contributes to the monocyte-macrophage lineage differentiation, increases the activity of macrophages, and promotes their cytotoxicity. Therefore, vitamin D enhances host defense against bacterial infections, as well as growth of tumor cells [20].

In 2007, Schauber et al. found that vitamin D can stimulate human skin cells to synthesize the antimicrobial peptide cathelicidin, which can enhance the innate immune function [21]. The active vitamin D-vitamin D receptor complex was found to influence Mycobacterium tuberculosis infection mainly by inhibiting the synthesis of IL-12 and γ-interferon, as well as the Th1 immune responses [22]. A meta-analysis study showed that the serum 25-hydroxyvitamin D concentrations were significantly lower in patients with tuberculosis than in the control group [23]. Vitamin D deficiency has also been found to be associated with increased incidence of respiratory diseases, such as influenza; Mycobacterium tuberculosis infection; and chronic respiratory diseases, such as cystic fibrosis, interstitial lung disease, and chronic obstructive pulmonary disease.

The active vitamin D has also been found to have inhibitory effects on transplant rejection. Studies on heart transplantation have shown that active vitamin D may be more effective than cyclosporine in prolonging the survival of the transplanted organ and will not increase the rate of infection [24]. In kidney transplantation, the active vitamin D also extends the viability of the transplanted kidney and reduces the progression of renal fibrosis [25]. The above antirejection effect occurs through the TGF-β/Smad3 pathway [26].

5. Antiapoptotic and Antifibrotic Effects of Vitamin D

In normal tissues, vitamin D plays an important role in regulating the proliferation by promoting apoptosis. For example, in breast tissue, vitamin D regulates apoptosis according to the requirements of the body at different physiological stages such as pregnancy and breastfeeding [27]. In addition to the normal tissues, vitamin D has been reported to be important in the regulation of hyperplasia in cancerous and noncancerous tissues via initiation of apoptosis in glioma, melanoma, and breast cancer cells [28]. In breast cancer cells, vitamin D induced apoptosis via interaction between Bcl2 and Bax [29]. In colorectal cancer, the transcription factor Snail reduces the expression of the vitamin D receptor, thereby influencing the progression of colon cancer cells [30]. The amount of vitamin D receptor is an important factor in determining its potency in the regulation of tumor growth.

In the nervous system, the active vitamin D affects the conduction of the motor neurons and synthesis of neurotrophic factors, thus preventing damages to the neurons [31].

Further, excess formation of keratin in psoriasis is due to the overexpression of TGF-α. Vitamin D helps in reducing the proliferation of keratinocytes, hence treating psoriasis by inhibiting the growth cycle of the TGF-α/EGFR (epidermal growth factor receptor) [32].

6. Vitamin D in Kidney Disease, Diabetes Mellitus, and Cardiovascular Disease

Active vitamin D has a negative feedback on the renin-angiotensin system, which plays a key role in regulating blood pressure, electrolyte levels, and volume status. When patients have low serum levels of active vitamin D, they may develop high blood pressure or diseases related to high plasma renin activity [33]. Studies on knockout mice lacking active vitamin D receptor expression revealed elevated levels of renin and angiotensin II in the blood, which in turn caused a significant increase in blood pressure, cardiac hypertrophy, and water retention [34].

Calcitriol, an analogue of the active vitamin D, exerted inhibitory effects on renal interstitial myofibroblasts and thereby inhibited the progression to renal interstitial fibrosis [35]. Several studies on nephropathy showed that active vitamin D protects the kidneys through its anti-inflammatory and antifibrotic effects [36, 37]. Vitamin D deficiency has also been found to be associated with earlier-onset and highly severe diabetes mellitus, presumably because of abnormal insulin secretion and immune dysfunctions. The condition of such diabetes patients can be improved by calcitriol supplementation [38]. A UK population-based study found that patients with type 1 diabetes had lower serum 25-hydroxyvitamin D concentrations than did healthy subjects of the same age. The study also found that the 3 main genes controlling the 25-hydroxyvitamin D metabolism are related to the incidence of type 1 diabetes [39]. Both in vitro and in vivo studies also showed that vitamin D could prevent the destruction of pancreatic beta-cells and reduce the incidence of autoimmune diabetes mellitus, possibly secondary to inhibition of proinflammatory cytokines, such as tumor necrosis factor (TNF-α) [5].

In the cardiac system, vitamin D maintains cardiovascular health by direct binding to vitamin D receptor on the myocardial cells, and thus regulating the hypertrophy of myocardial cells and the synthesis and release of atrial natriuretic peptide [40, 41]. Vitamin D has been shown to inhibit angiogenesis and increase matrix G1A protein synthesis and thus inhibit the synthesis of inflammatory cytokines such as tumor necrosis factor and interleukin [42]. On the other hand, vitamin D inhibits the calcification of blood vessels by regulating the activities of interleukins [43]. In patients with end-stage renal disease, vitamin D supplementation has been found to improve left ventricular function and muscle weakness, but the mechanism underlying this function is not known yet [11]. Vitamin D deficiency has been found to be associated with a variety of cardiovascular and other diseases, such as hypertension, diabetes mellitus, myocardial infarction, stroke, congestive heart failure, peripheral vascular disease, and atherosclerosis [12]. Therefore, the serum level of vitamin D is considered to be an important independent predictor of cardiovascular diseases [5].

7. Vitamin D in the Immune System

The interaction of vitamin D with the immune system is one of its most well-known effects [44]. The active vitamin D regulates innate and adaptive immune system, because its receptors are widely present on many immune cells, such as macrophages, dendritic cells, T cells, and B cells [45]. Vitamin D is thought to be able to activate cathelicidins, antimicrobial peptides present within the lysosomes of macrophages, and polymorphonuclear leukocytes [46]. Cathelicidins play a key role in innate immune defense against bacterial infections [47]. Cathelicidins regulate the transcription of vitamin D receptor as its gene promoter contains the functional response to vitamin D [48]. The active vitamin D regulates this antimicrobial peptide function in many different types of cells, including macrophages, keratinocytes, lung epithelial cells, placental trophoblast cells, and myeloid cell lines [21, 49, 50]. Therefore, active vitamin D has been found to inhibit the initiation of many diseases, such as experimental autoimmune encephalomyelitis, thyroiditis, type 1 diabetes mellitus, inflammatory bowel disease, systemic lupus erythematosus, and Lyme arthritis [16, 51].

In vitro studies on systemic lupus erythematosus revealed that the abnormal immune response may be reversed by addition of vitamin D; therefore, vitamin D deficiency is considered to be associated with loss of immune tolerance [52]. Studies on rheumatoid arthritis found that the disease activity is negatively correlated with serum vitamin D concentration, and such a correlation is independent of the parathyroid function [53].

8. Vitamin D and Cancer

Several studies have shown that vitamin D plays a protective role in several types of cancer, such as prostate, breast, and colon cancer [10]. Vitamin D has also been found to inhibit proliferation of a variety of human leukemia cell lines and induce differentiation of normal and leukemic myeloid precursor, thereby increasing maturation and decreasing aggressiveness of potential leukemic cells. Therefore, vitamin D is helpful in the treatment of leukemia and other myeloproliferative disorders [54].

The state of knowledge on the protective effects in cancer of vitamin D is as follows.

(1)Active vitamin D promotes the transcription of the cyclin-dependent kinase inhibitor p21 [18]. This is sufficient to suppress growth of cells of the monocyte-macrophage lineage and promote their differentiation.(2)Active vitamin D induces the synthesis of the cyclin-dependent kinase inhibitor p27 [55].(3)The proliferation of tumor cells is due to the overexpression of the TGF-α/EGFR pathway. Active vitamin D could inhibit the TGF-α/EGFR growth pathway [32].(4)In human epithelial cell tumors, C/EBPβ is considered to be effective in the inhibition of the carcinogenic cell cycle protein D1 [56]. In contrast, the C/EBPβ isoform LIP can enhance the activity of the carcinogenic cyclin D1 and induce cell growth. Therefore, the proliferative property of human tumors is inversely correlated to the intracellular C/EBPβ-to-LIP ratio [57]. The active vitamin D can induce the expression of C/EBPβ and prevent the proliferation of LIP epidermal growth factor receptor, thus reducing the occurrence of EGFR-driven related cancers [58].(5)Vitamin D plays a major role in cell metabolism as it regulates cell maturation, differentiation, and apoptosis [10]. These features are related to the suppressed expression of antiapoptotic proteins such as Bcl2 in cancer cells and arrest of cell cycle in G0/G1, which reduces the rate of proliferation [59]. Vitamin D was also found to have anti-inflammatory effects that can delay and prevent the development of cancers [60].

Studies have found that the adequacy of the content of vitamin D in the body is an important factor in predicting several types of cancer prognosis and mortality [5].

9. Conclusions

In the past decades, the function of vitamin D has been more deeply understood. The discovery of the vitamin D receptor enabled further investigations on the association of acute and chronic diseases with vitamin D deficiency. The pleiotropic effects of vitamin D and associated mechanisms are summarized in Table 1. In addition, the paracrine and autocrine effects of vitamin D have a protective role in many diseases. Therefore, the application of vitamin D in disease treatment and prevention should be pursued.

Table 1: The pleiotropic effects of vitamin D and associated mechanisms and diseases.

Pleiotropic effects
Mechanism
Associated diseases

Anti-inflammation
(1) affects the differentiation of active CD4⁺ T-cells

(2) enhances the inhibitory function of T-cells

(3) promotes differentiation of monocyte into mature macrophages by inducing p21

(4) induces C/EBPβ which contribute to the monocyte-macrophage lineage differentiation, increase the activity of macrophages, and promote their antibacterial and antiviral activities

(5) inhibits the synthesis of IL-12, γ-interferon, and Th1 immune responses

(6) inhibits TGF-β/Smad3 pathway on transplant rejection
(1) recurrent infections in rickets or CKD patients

(2) increased incidence of respiratory diseases, such as influenza, mycobacterium tuberculosis, and chronic respiratory diseases, such as cystic fibrosis, interstitial lung disease, and chronic obstructive pulmonary disease

Antiapoptosis and antfibrosis
(1) induce apoptosis via interaction between Bcl2 and Bax in breast cancer cells

(2) affect the conduction of the motor neurons and synthesis of neurotrophic factors, thus preventing damage of the neurons

(3) inhibit the growth cycle of the TGF-α/EGFR and reduce the proliferation of keratinocytes
(1) progression of cancer cells

(2) excess formation of keratin in psoriasis

Cardiovascular diseases
(1) have negative feedback on renin-angiotensin system in regulating blood pressure, electrolyte and volume status

(2) have direct binding to vitamin D receptor on the myocardial cells and regulate the hypertrophy of myocardial cells

(3) have synthesis and release of atrial natriuretic peptide

(4) inhibit angiogenesis and increase matrix G1A protein synthesis, thus inhibiting inflammatory cytokines such as tumor necrosis factor and interleukin

(5) inhibit calcification of blood vessels by regulating interleukins
(1) hypertension, water retention

(2) cardiac hypertrophy, myocardial infarction, stroke, congestive heart failure, peripheral vascular disease, and atherosclerosis

Kidney diseases
(1) inhibit renal interstitial myofibroblasts, inhibiting the progression to renal interstitial fibrosis
(1) renal fibrosis

Diabetes mellitus (DM)
(1) prevents the destruction of pancreatic beta-cells

(2) reduces autoimmune diabetes mellitus, possibly secondary to inhibition of proinflammatory cytokines, such as tumor necrosis factor (TNF-α)
(1) earlier onset and more severe DM

(2) type I DM

Immune system
(1) activates cathelicidins, an antimicrobial peptide within the lysosomes of macrophages and polymorphonuclear leukocytes
(1) increases initiation of experimental autoimmune encephalomyelitis, thyroiditis, type 1 diabetes mellitus, inflammatory bowel disease, systemic lupus erythematosus, and Lyme arthritis

(2) increases the disease activity of rheumatoid arthritis

Cancers
(1) promote the transcription of cyclin-dependent kinase inhibitors, p21

(2) induce synthesis of the cyclin-dependent kinase inhibitors, p27

(3) inhibit the TGF-α/EGFR growth pathway

(4) induce the expression of C/EBPβ and prevent proliferation of LIP epidermal growth factor receptor, thus reducing EGFR-driven related cancers

(5) suppress expression of anti-apoptotic proteins such as Bcl2 of cancer cells, arrest of cell cycle in G0/G1, thus slowing proliferation of cancer cells
(1) prostate, breast, and colon cancers

(2) leukemia and other myeloproliferative disorders

References

J. A. Eisman, T. J. Martin, I. MacIntyre, and J. M. Moseley, “1,25-DihydroxyVitamin D receptor in breast cancer cells,” The Lancet, vol. 2, no. 1, pp. 1335–1336, 1979.

M. F. Holick, “Medical progress: Vitamin D deficiency,” The New England Journal of Medicine, vol. 357, no. 3, pp. 266–281, 2007.

P. Muszkat, M. B. R. Camargo, L. H. M. Griz, and M. Lazaretti-Castro, “Evidence-based non-skeletal actions of Vitamin D,” Arquivos Brasileiros de Endocrinologia e Metabologia, vol. 54, no. 2, pp. 110–117, 2010.

V. V. Khadilkar and A. V. Khadilkar, “Use of Vitamin D in various disorders,” Indian Journal of Pediatrics, vol. 80, no. 3, pp. 215–218, 2013.

A. Zittermann and J. F. Gummert, “Nonclassical Vitamin D actions,” Nutrients, vol. 2, no. 4, pp. 408–425, 2010.

M. J. McKenna, “Differences in Vitamin D status between countries in young adults and the elderly,” American Journal of Medicine, vol. 93, no. 1, pp. 69–77, 1992.

D. M. Antoniucci, T. Yamashita, and A. A. Portale, “Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 8, pp. 3144–3149, 2006.

A. Zittermann and R. Koerfer, “Protective and toxic effects of Vitamin D on vascular calcification: clinical implications,” Molecular Aspects of Medicine, vol. 29, no. 6, pp. 423–432, 2008.

M. Gallieni, S. Kamimura, A. Ahmed et al., “Kinetics of monocyte 1α-hydroxylase in renal failure,” American Journal of Physiology, vol. 268, no. 4, pp. F746–F753, 1995.

A. Zittermann, “Vitamin D in preventive medicine: are we ignoring the evidence?” British Journal of Nutrition, vol. 89, no. 5, pp. 552–572, 2003.

J. Selles, V. Massheimer, G. Santillan, M. J. Marinissen, and R. Boland, “Effects of calcitriol and its analogues, calcipotriol (MC 903) and 20- epi-1α,25-dihydroxyVitamin D3 (MC 1288), on calcium influx and DNA synthesis in cultured muscle cells,” Biochemical Pharmacology, vol. 53, no. 12, pp. 1807–1814, 1997.

C. McGreevy and D. Williams, “New insights about Vitamin D and cardiovascular disease: a narrative review,” Annals of Internal Medicine, vol. 155, no. 12, pp. 820–826, 2011.

R. Bouillon, G. Carmeliet, L. Verlinden et al., “Vitamin D and human health: lessons from Vitamin D receptor null mice,” Endocrine Reviews, vol. 29, no. 6, pp. 726–776, 2008.

M. Hewison, F. Burke, K. N. Evans et al., “Extra-renal 25-hydroxyVitamin D3-1α-hydroxylase in human health and disease,” Journal of Steroid Biochemistry and Molecular Biology, vol. 103, no. 3–5, pp. 316–321, 2007.

A. Zittermann, G. Tenderich, and R. Koerfer, “Vitamin D and the adaptive immune system with special emphasis to allergic reactions and allograft rejection,” Inflammation and Allergy, vol. 8, no. 2, pp. 161–168, 2009.

C. E. Hayes, F. E. Nashold, K. M. Spach, and L. B. Pedersen, “The immunological functions of the Vitamin D endocrine system.,” Cellular and Molecular Biology, vol. 49, no. 2, pp. 277–300, 2003.

M. Asaka, H. Iida, K. Izumino, and S. Sasayama, “Depressed natural killer cell activity in uremia. Evidence for immunosuppressive factor in uremic sera,” Nephron, vol. 49, no. 4, pp. 291–295, 1988.

M. Liu, M. Lee, M. Cohen, M. Bommakanti, and L. P. Freedman, “Transcriptional activation of the Cdk inhibitor p21 by Vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937,” Genes and Development, vol. 10, no. 2, pp. 142–153, 1996.

B. Gorgoni, D. Maritano, P. Marthyn, M. Righi, and V. Poli, “C/EBPβ gene inactivation causes both impaired and enhanced gene expression and inverse regulation of IL-12 p40 and p35 mRNAs in macrophages,” Journal of Immunology, vol. 168, no. 8, pp. 4055–4062, 2002.

Y. Ji and G. P. Studzinski, “Retinoblastoma protein and CCAAT/enhancer-binding protein beta are required for 1,25-dihydroxyVitamin D3-induced monocytic differentiation of HL60 cells,” Cancer Research, vol. 64, no. 1, pp. 370–377, 2004.

J. Schauber, R. A. Dorschner, A. B. Coda et al., “Injury enhances TLR2 function and antimicrobial peptide expression through a Vitamin D-dependent mechanism,” Journal of Clinical Investigation, vol. 117, no. 3, pp. 803–811, 2007.

J. O'Kelly, J. Hisatake, Y. Hisatake, J. Bishop, A. Norman, and H. Phillip Koeffler, “Normal myelopoiesis but abnormal T lymphocyte responses in Vitamin D receptor knockout mice,” Journal of Clinical Investigation, vol. 109, no. 8, pp. 1091–1099, 2002.

K. E. Nnoaham and A. Clarke, “Low serum Vitamin D levels and tuberculosis: a systematic review and meta-analysis,” International Journal of Epidemiology, vol. 37, no. 1, pp. 113–119, 2008.

D. A. Hullett, M. T. Cantorna, C. Redaelli et al., “Prolongation of allograft survival by 1,25-dihydroxyVitamin D3,” Transplantation, vol. 66, no. 7, pp. 824–828, 1998.

J. K. Aschenbrenner, H. W. Sollinger, B. N. Becker, and D. A. Hullett, “1,25-(OH(2))D(3) alters the transforming growth factor beta signaling pathway in renal tissue,” Journal of Surgical Research, vol. 100, no. 2, pp. 171–175, 2001.

J. Yanagisawa, Y. Yanagi, Y. Masuhiro et al., “Convergence of transforming growth factor-β and Vitamin D signaling pathways on SMAD transcriptional coactivators,” Science, vol. 283, no. 5406, pp. 1317–1321, 1999.

G. M. Zinser and J. Welsh, “Accelerated mammary gland development during pregnancy and delayed postlactational involution in Vitamin D3 receptor null mice,” Molecular Endocrinology, vol. 18, no. 9, pp. 2208–2223, 2004.

M. E. Valrance and J. Welsh, “Breast cancer cell regulation by high-dose Vitamin D compounds in the absence of nuclear Vitamin D receptor,” Journal of Steroid Biochemistry and Molecular Biology, vol. 89-90, pp. 221–225, 2004.

N. Wagner, K. Wagner, G. Schley, L. Badiali, H. Theres, and H. Scholz, “1,25-DihydroxyVitamin D3-induced apoptosis of retinoblastoma cells is associated with reciprocal changes of Bcl-2 and bax,” Experimental Eye Research, vol. 77, no. 1, pp. 1–9, 2003.

H. G. Palmer, M. J. Larriba, J. M. Garcia, et al., “The transcription factor SNAIL represses Vitamin D receptor expression and responsiveness in human colon cancer,” Nature Medicine, vol. 10, no. 36, pp. 917–919, 2004.

J. Brown, J. I. Bianco, J. J. McGrath, and D. W. Eyles, “1,25-DihydroxyVitamin D3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons,” Neuroscience Letters, vol. 343, no. 2, pp. 139–143, 2003.

J. B. Cordero, M. Cozzolino, Y. Lu et al., “1,25-DihydroxyVitamin D down-regulates cell membrane growth- and nuclear growth-promoting signals by the epidermal growth factor receptor,” The Journal of Biological Chemistry, vol. 277, no. 41, pp. 38965–38971, 2002.

Y. C. Li, “Vitamin D regulation of the renin-angiotensin system,” Journal of Cellular Biochemistry, vol. 88, no. 2, pp. 327–331, 2003.

Y. C. Li, J. Kong, M. Wei, Z. Chen, S. Q. Liu, and L. Cao, “1,25-DihydroxyVitamin D3 is a negative endocrine regulator of the renin-angiotensin system,” Journal of Clinical Investigation, vol. 110, no. 2, pp. 229–238, 2002.

V. N. Foltyn, I. Bendikov, J. De Miranda et al., “Serine racemase modulates intracellular D-serine levels through an α,β-elimination activity,” The Journal of Biological Chemistry, vol. 280, no. 3, pp. 1754–1763, 2005.

X. Tan, Y. Li, and Y. Liu, “Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy,” Journal of the American Society of Nephrology, vol. 17, no. 12, pp. 3382–3393, 2006.

X. Tan, X. Wen, and Y. Liu, “Paricalcitol inhibits renal inflammation by promoting Vitamin D receptor-mediated sequestration of NF-κB signaling,” Journal of the American Society of Nephrology, vol. 19, no. 9, pp. 1741–1752, 2008.

B. S. Chertow, W. I. Sivita, and N. G. Baranetsky, “Cellular mechanisms of insulin release: the effects of Vitamin D deficiency and repletion on rat insulin secretion,” Endocrinology, vol. 113, no. 4, pp. 1511–1518, 1983.

J. D. Cooper, D. J. Smyth, N. M. Walker et al., “Inherited variation in Vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes,” Diabetes, vol. 60, no. 5, pp. 1624–1631, 2011.

J. Wu, M. Garami, T. Cheng, and D. G. Gardner, “1,25 (OH)2 Vitamin D3 and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes,” Journal of Clinical Investigation, vol. 97, no. 7, pp. 1577–1588, 1996.

J. Wu, M. Garami, L. Cao, Q. Li, and D. G. Gardner, “1,25(OH)2D3 suppresses expression and secretion of atrial natriuretic peptide from cardiac myocytes,” American Journal of Physiology, vol. 268, no. 6, pp. E1108–E1113, 1995.

K. Müller, P. M. Haahr, M. Diamant, K. Rieneck, A. Kharazmi, and K. Bendtzen, “1,25-dihydroxyVitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level,” Cytokine, vol. 4, no. 6, pp. 506–512, 1992.

L. J. Schurgers, P. E. P. Dissel, H. M. H. Spronk et al., “Role of Vitamin K and Vitamin K-dependent proteins in vascular calcification,” Zeitschrift fur Kardiologie, vol. 90, no. 3, pp. 57–63, 2001.

A. R. Martineau, F. U. Honecker, R. J. Wilkinson, and C. J. Griffiths, “Vitamin D in the treatment of pulmonary tuberculosis,” Journal of Steroid Biochemistry and Molecular Biology, vol. 103, no. 3–5, pp. 793–798, 2007.

E. Toubi and Y. Shoenfeld, “The role of Vitamin D in regulating immune responses,” Israel Medical Association Journal, vol. 12, no. 3, pp. 174–175, 2010.

S. Segaert, “Vitamin D regulation of cathelicidin in the skin: toward a renaissance of Vitamin D in dermatology?” Journal of Investigative Dermatology, vol. 128, no. 4, pp. 773–775, 2008.

V. Nizet, T. Ohtake, X. Lauth et al., “Innate antimicrobial peptide protects the skin from invasive bacterial infection,” Nature, vol. 414, no. 6862, pp. 454–457, 2001.

A. F. Gombart, N. Borregaard, and H. P. Koeffler, “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,” The FASEB Journal, vol. 19, no. 9, pp. 1067–1077, 2005.

S. Yim, P. Dhawan, C. Ragunath, S. Christakos, and G. Diamond, “Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyVitamin D3,” Journal of Cystic Fibrosis, vol. 6, no. 6, pp. 403–410, 2007.

N. Liu, A. T. Kaplan, J. Low et al., “Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway1,” Biology of Reproduction, vol. 80, no. 3, pp. 398–406, 2009.

L. Adorini, G. Penna, N. Giarratana et al., “Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands,” Journal of Steroid Biochemistry and Molecular Biology, vol. 89-90, pp. 437–441, 2004.

D. Kamen and C. Aranow, “Vitamin D in systemic lupus erythematosus,” Current Opinion in Rheumatology, vol. 20, no. 5, pp. 532–537, 2008.

J. Moghimi, A. Sadeghi, M. Malek, and R. Ghorbani, “Relationship between disease activity and serum levels of Vitamin D and parathyroid hormone in rheumatoid arthritis,” Endocrine Regulations, vol. 46, no. 82, pp. 61–66, 2012.

E. Abe, C. Miyaura, and H. Sakagami, “Differentiation of mouse myeloid leukemia cells induced by 1α,25-dihydroxyVitamin D3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 8 I, pp. 4990–4994, 1981.

P. Li, C. Li, X. Zhao, X. Zhang, S. V. Nicosia, and W. Bai, “p27Kip1 stabilization and G1 arrest by 1,25-dihydroxyVitamin D3 in ovarian cancer cells mediated through down-regulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase,” The Journal of Biological Chemistry, vol. 279, no. 24, pp. 25260–25267, 2004.

J. Lamb, S. Ramaswamy, H. L. Ford et al., “A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer,” Cell, vol. 114, no. 3, pp. 323–334, 2003.

C. A. Zahnow, “CCAAT/enhancer binding proteins in normal mammary development and breast cancer,” Breast Cancer Research, vol. 4, no. 3, pp. 113–121, 2002.

B. R. Baldwin, N. A. Timchenko, and C. A. Zahnow, “Epidermal growth factor receptor stimulation activates the RNA binding protein CUG-BP1 and increases expression of C/EBPbeta-LIP in mammary epithelial cells,” Molecular and Cellular Biology, vol. 24, no. 9, pp. 3682–3691, 2004.

J. Welsh, “Targets of Vitamin D receptor signaling in the mammary gland,” Journal of Bone and Mineral Research, vol. 22, no. 2, pp. V86–V90, 2007.

A. V. Krishnan, D. L. Trump, C. S. Johnson, and D. Feldman, “The role of Vitamin D in cancer prevention and treatment,” Endocrinology and Metabolism Clinics of North America, vol. 39, no. 2, pp. 401–418, 2010.