1,25 dihydroxy-vitamin D3 (calcitriol or 1,25-dihydroxycholecalciferol) is known to regulate calcium and phosphorus metabolism, playing a major role in bone homeostasis. Over the past few years, research into non-skeletal effects of calcitriol has been emerging. It is involved in hormone release from endocrine glands, modulation of the immune system and affects cardiovascular, reproductive and neural functions in the body. Calcitriol also has anti- cancer effects against leukemia, colon, kidney, breast and prostate cancers.1 The discovery of nuclear vitamin D receptors (VDRs) on most body cells, and their involvement in cell differentiation, proliferation and immunomodulation has resulted in greater depth of research in to the study of vitamin D and its' active form calcitriol. Vitamin D3 is mainly synthesised in the skin and obtained through food to a smaller extent. It is hydroxylated to 25-hydroxyvitamin D (25(OH)D or calcidiol) in the liver and stored to be released in to circulation when required. In the kidney calcidiol is converted to calcitriol, the active form by the enzyme 25-hydroxyvitamin D3 1Î±-hydroxylase. Calcitriol enters circulation and travels to target tissues and bind VDRs. Acting through these VDRs, calcitriol is able to alter nuclear transcription of various genes, altering cellular function.
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VDRs form a heterodimer with retinoid X receptors (RXRs). "RXR is a nuclear receptor for 9-cis retinoic acid" and is essential for the activity of the VDR. In the absence of calcitriol (VDR ligand), VDRs remain in the cytoplasm. In the presence of VDR ligands, RXR-VDR heterodimerization occurs and this is translocated in to the nucleus. The heterodimer bind vitamin D3 response elements (VDREs), in promoter regions of vitamin D3 responsive genes. Transcription of these genes can be up-regulate or down-regulate (through binding on to negative VDREs) and also antagonise the effects of other transcription factors. Genes that are up-regulated include "osteocalcin, osteopontin, receptor activator of NF-ÎºB ligand (RANKL), and carbonic anhydrase II", involved in bone homeostasis. More interestingly other up-regulated genes such as "cell adhesion molecule Î²3 integrin, tumor suppressor p21, calbindin-9k, 24-hydroxylase and human CYP3A4" help to explain non-skeletal effects of vitamin D3.14 Transcription factor antagonism is associated with the decreased amount of IL-2, IL-12, TNF-Î± and IFN-Î³ produced.14
Previous work on the link between vitamin D and the immune system were based upon disease states where calcitriol synthesis was deregulated. Recent studies have shown an effect on the normal regulation of the immune system. Calcitriol targets a variety of immune cells of the innate and adaptive immune system. These include monocytes, macrophages, dendritic cells (DCs), T and B lymphocytes via VDRs. Up-regulation of anti- microbial peptides such as cathelicidin is induced, to enable bacterial clearance. There is a direct effect on T cell activation and on the phenotype and function of DCs.5 Th2/ Treg (T regulatory cells) responses are stimulated while Th1 / Th17 responses are inhibited. Interestingly these immune cells as well as macrophages contain the vitamin D3 converting enzyme (25-hydroxyvitamin D3 1Î±-hydroxylase) which allows local conversion of vitamin D3 in to its' active form, calcitriol in the immune system. They act in an autocrine/ paracrine fashion converting the precursor calcidiol in circulation to calcitriol.4 This enzyme in the kidney is regulated by the parathyroid hormone (PTH), while it is stimulated by cytokines in macrophages, DCs and keratinocytes. PTH does not seem to have any effect on these latter cells and the product (calcitriol) does not cause direct feedback inhibition.8 So vitamin D3 and 25-hydroxyvitamin D3 1Î±-hydroxylase plays an important role in maintaining immune homeostasis. 3
T and B lymphocytes are responsible for eliciting an adaptive immune response, after foreign antigens are presented to them by macrophages and DCs. Calcitriol is able to suppress proliferation and immunoglobulin production by B cells and also slow down B cell differentiation in to plasma cells.
Th1 cell proliferation is inhibited, through a decrease in interferon gamma (IFN-Î³) which directly decreases antigen presentation and recruitment of T cells. A decrease in interleukin (IL)- 2 production also occurs, inhibiting T cell proliferation.6
Th2 responses are stimulated with increased IL-4, IL-5, and IL-10 production, while Treg cells are stimulated through increased FoxP3 expression as well as IL-10 production (this helps to block Th1 development). Calcitriol is able to decrease expression of co- stimulatory molecules such as CD40, CD80, CD86 in dendritic cells. This decreases their ability to secrete IL-12 which plays a role in Th1 cell development. In terms of Th17 cell development, calcitriol inhibits IL-23 and IL-6 required for Th17 cell development and function.6
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Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) (experimental model of MS) is a major research area implicated with vitamin D as the 25-hydroxyvitamin D3 1Î±-hydroxylase enzyme is also present in neural tissues. Treatment of EAE with calcitriol has shown to decrease disease progression by affecting dendritic cell, T lymphocyte and macrophage activity. MS, an autoimmune disease is caused by demyelination of axons in the CNS (central nervous system) and inflammation caused by auto-reactive, myelin-specific T lymphocytes infiltrating the BBB (blood- brain barrier). B cells are also thought to be involved. These cells start off the inflammatory process with cytokine and antibody production as well as resulting in macrophage recruitment. Th1 cells have been studied to induce EAE, promoted by IL-12 and macrophage infiltration. This causes the inflammation and tissue damage in the brain. So the amount of vitamin D3 in the body and the presence of VDRs, play a major role in disease as immune cells are capable of being manipulated by calcitriol.12 To add to this, new research indicates that Th17 cell responses may play a key role in increased disease progression of MS. This response is driven by IL-23 and has been demonstrated using EAE.
The adaptive immune response suppression by calcitriol can be beneficial in other autoimmune diseases such as inflammatory arthritis, autoimmune diabetes and inflammatory bowel disease. TLRs (Toll- like receptors) on polymorphonuclear cells (PMNs), monocytes and macrophages become activated by specific membrane patterns (PAMPs) of infectious agents. This activation results in antimicrobial peptide (cathelicidin) production also promoted by calcitriol. It has been proven that macrophages and epithelial cells both respond to and possess VDRs and the enzyme 25-hydroxyvitamin D3 1Î±-hydroxylase. Stimulation of TLR2 on macrophages and keratinocytes on the epidermis after a wound, cause increased expression of 25-hydroxyvitamin D3 1Î±-hydroxylase enzyme, which results in increased production of calcitriol in the presence of adequate substrate calcidiol. This increased expression of the enzyme as well as VDRs during infection has been demonstrated by the stimulation of TLR2/1, using lipoproteins produced by M. Tuberculosis. The infection can be cleared by the increased amount of cathelicidins produced.8
Anti- proliferative effects of calcitriol on cancer cells occur though nuclear VDRs. It arrests the cell cycle in G0/ G1 phase and also up-regulate certain cell cycle inhibitors such as p21waf/cip1 and p27kip1. These genes have vitamin D responsive elements in their promoter regions and govern apoptosis, differentiation and angiogenesis (growth of new blood vessels).13 Cell arrest at G2/ M phase can also be directly inducted through the GADD45Î± gene which arrest growth, and damage DNA.9 Many studies have proved the reduction of colorectal, skin, prostate and breast cancer risks in the presence of increased calcidiol. Anti- inflammatory effects such as "suppression of prostaglandin action, inhibition of p38 stress kinase signaling, and the subsequent production of proinflammatory cytokines and inhibition of NF-ÎºB signaling" has been shown.10 Calcitriol also decreases the expression of aromatase, an enzyme involved in oestrogen synthesis which increases proliferation of breast cancer cells. This occurs through direct transcriptional inhibition and also indirectly through reduction in prostaglandins, which usually stimulate aromatase transcription. Suppression of tumor manifestation and metastasis is an important role of calcitriol in cancer. There is a strongly link between vitamin D deficiency and increased risk of cancer.11 In colon cancer cells, anti proliferative effect are produced by inhibition of the Wnt/Î²-catenin pathway. Calcitriol-VDR complex binds Î²-catenin and prevent induction of cell proliferation.13
Increased risk of diabetes (type 1 and 2), hypertension, cardiovascular disease and inflammation is thought to have a link to increased PTH (parathyroid hormone) levels as calcitriol affect parathyroid cells. This increases insulin resistance in conditions of vitamin D deficiency. There is also evidence of schizophrenia, osteoporosis and chronic musculoskeletal pain development due to vitamin D deficiency.11 The pancreas increases insulin production by Î² cells as they respond to calcitriol due to the presence of VDR receptors and 1Î±-hydroxylase enzyme. Another effect of calcitriol is a decrease in renin production by the kidneys. This is thought to have an effect on controlling hypertension. In addition to this, decreasing "the proliferation of myocardial and vascular smooth muscle cells" and lowering LDL (low density lipoproteins) levels while increasing HDL (high density lipoproteins) is thought to decrease the risk of atherosclerosis and heart failure.13
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Therapeutic effects of vitamin D3 and its' analogues on osteoporosis, psoriasis, and secondary hyperparathyroidism has been extensively researched on. Topical application of calcirtiol and oral administration of 1Î±-hydroxyvitamin D3 has been successful in the treatment of psoriasis through action on keratinocytes. These VDR ligands down- regulate proliferative genes such as the epidermal growth factor receptor and c-myc (in keratinocytes), and K16 (in psoriatic plaques).14 Oral administration of calcitriol for treatment of osteoporosis works by increasing calcium absorption through intestinal cells. In the treatment of hyperparathyroidism; parathyroid cells, osteoblasts and keratinocytes, involved in mineral homeostasis become down-regulated.14 Treatment of depression and MS is also another therapeutic use of vitamin D3 and its' derivatives.
The presence of VDRs and hydroxylases which convert calcidiol to calcitriol in most cells of the body allows vitamin D to have an effect on cells locally. Vitamin D in its' active form calcitriol plays a major role in immune regulation. It has anti- proliferative, pro-apoptotic actions on malignant cancer cells and tumours. It should be noted that some cancers are able to resist the anti-proliferative effects of calcitriol by up-regulating the enzyme 24-hydroxylase which breaks down calcitriol. Nevertheless from many studies it clear that vitamin D plays an important role in reducing the risk of many disease and its' progression. It has been linked to multiple sclerosis, schizophrenia, rheumatoid arthritis, hypertension, heart disease, diabetes and cancer. Non- skeletal effect of calcitriol is also thought to be essential in the normal functioning of the body and there is growing interest in this field to assess whether vitamin D and its' analogues could be used in the treatment of many diseases.