Assignment No.

2013

The Role of Vitamin D in Calcium Homeostasis, Immunity and Cancer

Fakhruddin Babiker Ali Calcium Homeostasis The blood level of Ca2+ is very closely regulated: even small changes in Ca2+ concentration can be fatal. The active form of vitamin D (calcitriol) regulates low plasma concentration of Ca2+ by action at the three major targets, namely intestine, bone and kidney. And that is by: 1Stimulating the intestinal absorption of Ca2+ by independent mechanisms 2Stimulating the transport of Ca2+ from the bone fluid compartment to the extracellular fluid compartment 3Facilitating the renal re-absorption of Ca2+ The normal concentration of Ca2+ in the serum of most species is about 10 mg/dl; the vitamin D dependent homeostatic system responds to perturbations of that level by modulating Ca2+ entry to and exit from the plasma via three previous mechanisms. When the serum Ca2+ concentration falls below the target level PTH is secreted by the parathyroid glands. The kidney responds to PTH in two ways: phosphate dieresis and stimulation of 25-OH-vitamin D 1-hydroxylase. The latter effect increases the production of 1, 25-(OH) 2-D3 (calcitriol), which acts (probably by inducing calbindin) in the intestine to increase the enteric absorption of both Ca2+ and phosphate. Also calcitriol acts jointly with PTH in bone to promote the mobilization of Ca2+ and phosphate. These responses collectively will help maintain the concentrations of Ca2+ and phosphate in plasma. On other hands, when serum concentration of Ca2+ is elevated, calcitonin (CT) is secreted to suppress bone mobilization and possibly increases renal excretion of both Ca2+ and phosphate. Here in these situations 25-OH-vitamin D 1-hydroxylase will be feedback inhibited by calcitriol and may actually be converted to the catalysis of the 24hydroxylation of 25-OH-D3.

Vitamin D in Calcium Homeostasis

The Role of Vitamin D in Calcium Homeostasis, Immunity and Cancer

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Assignment No. 3

2013

Immunity That vitamin D functions in immunity is indicated by the identification of VDRs in most immune cells as well as the demonstration of effects of calcitriol on the functional activities of those cells. This includes the inhibition of immunoglobulin secretion by B lymphocytes and the inhibition of production of interleukins 2 (IL-2) and 12 (IL-12), IL-2 receptor (IL2R), granulocyte-macrophage colony-stimulating factor, and interferon- by T cells, and the inhibition of accessory cell and antigen-presenting cell activities. In addition, calcitriol has been found to enhance macrophage and monocyte phagocytosis, bacterial killing, and heat shock protein production. The active metabolite calcitriol has also been shown in vitro to suppress the antigen-presenting capacity of macrophages, apparently by reducing the expression of adhesion molecules necessary for full T cell stimulation. Thus, calcitriol has been found to suppress the development of various autoimmune diseases and to prolong the survival of allografts. These effects appear to depend on VDRs, which mediate the calcitriol signal to upregulate natural defense reactions by enhancing the functions of monocytes and macrophages. Vitamin D deficiency has been associated with inflammation; studies have shown the circulating marker of inflammation, C-reactive protein, to be inversely correlated with serum concentrations of 25-OH-D3, and decreased in response to vitamin D treatment. The active metabolite calcitriol is also known to downregulate the production of pro-inflammatory cytokines by immune cells. However, that VDR-knockout mice show no immune abnormalities suggests that this function of the vitamin must be selective, depending on the nature of the immune challenge, or simply part of a higly redundant system.

The Immunomodulatory Effects of Vitamin D

The Role of Vitamin D in Calcium Homeostasis, Immunity and Cancer

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Assignment No. 3

2013

Cancer Over the last 30 years, more and more evidence has accumulated that shows higher vitamin D status intake or higher 25-hydroxyvitamin D levels may prevent cancer. And Most of the work done so far is either from cancer cells using calcitriol (active vitamin D) or from associations drawn between estimated sunlight exposure, vitamin D intake, or serum 25-hydroxy vitamin D levels and cancer risk in groups of people. And some of the most important capabilities of calcitriol seem to include the following: - Suppressing the proliferation of cells; cancer arises from abnormal cell proliferation - Promoting the death of abnormal cells that may become cancerous - Preventing blood vessels from forming in a developing tumor, which keeps nutrients from the tumor and prevents it from getting bigger - Stopping cancer cells from spreading to other parts of the body, thereby preventing metastases, the spread of cancer to healthy organs That vitamin D may be protective against colon cancer is supported by the finding that cultured colonocytes have a high 1-hydroxylase capacity, converting 5 to 10% of 25-OH-D3 to the active metabolite. Studies with a variety of cancer cell lines have shown that 1,25(OH)2-D3 can inhibit cell proliferation, induce cell differentiation, and induce apoptosis. Physiological concentrations of 25-OH-D3 inhibit mammary cells, which can also produce 1, 25-(OH) 2-D3. Presumably, these effects result from the induction of gene expression involved in the regulation of cell proliferation. In human leukemic cells, 1, 25-(OH) 2-D3 has been found to suppress cell division and induce differentiation by downregulating expression of the protooncogene c-myc. Thus, it has been proposed that this effect serves to bypass the cell cycle control (via synthesis or nuclear association) of c-myc. The antiproliferative effects of vitamin D may also involve its effects on cellular Ca2+status and availability. Studies have shown that 1,25-(OH)2-D3can both attenuate the growth of rapidly dividing colonic tumor cells94and reverse colonocytes from a malignant to a normal phenotype. These effects depend on binding of the vitamer to VDRs and may involve opening of Ca2+channels, leading to rapid reductions in the intracellular Ca2+level, thus inducing apoptosis. The mammary gland expresses VDR where the liganded receptor appears to function to oppose estrogen-driven proliferation and maintain differentiation. In that tissue 1, 25-(OH) 2-D3 has been shown to reduce the invasiveness of cancer cells and to inhibit angiogenesis. It has been suggested that polymorphisms in VDR may be associated with cancer risk; however, a recent meta-analysis indicated that such polymorphisms are unlikely to be major determinants of risk for at least prostate cancer. The story on vitamin D and cancer is still ongoing and there are still a lot of gaps in our understanding; however, assuming that low vitamin D causes cancer, some researchers estimate that more than 50,000 premature deaths from cancer could be prevented each year in the United States if people maintained sufficient levels of 25-hydroxyvitamin D in their blood.

The Role of Vitamin D in Calcium Homeostasis, Immunity and Cancer

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