Role of vitamin D in the immune system: D Vitamininin immun Sistemdeki Rolu.
Vitamin D is suggested to be an important immune system regulator. 1,25 dihydroxyvitamin D (1,25(OH)2D3), which is the active form of vitamin D, decreases the proliferation of purified 1-helper (Th)1 cells as well as the production of interferon (IFN)[gamma], interleukin (IL)-2, IL-5 and tumor necrosis factor-alpha (TNF-) [alpha]. In Th2 cells, 1,25 (OH)2D3 stimulates IL-4 and transforming growth factor TGF production, which in turn may suppress inflammatory T cell activity. In the absence of vitamin D signaling, the T cell compartment has a potentially stronger Thl phenotype. Furthermore, 1,2510H)2D3 inhibits dendritic cell (DC) differentiation and maturation, leading to down-regulated expression of major histocompatibility complex class II molecules (MHC-Il), co-stimulatory molecules and IL-12; enhances IL-10 production and promotes DC apoptosis. Because of these effects, 1,25(0H)2D3 inhibits DC-dependent T cell activation. In vitro, it is determined that 1,25(OH)2D3 stimulates phagocytosis and killing of bacteria by macrophages, but suppresses the antigen presenting capacity of these cells and dendritic cells. Additionally, Chen et al. have suggested that vitamin D might have a role in regulating antibody production. They have found that 1,25(OH)2D3 not only inhibits activated B cell proliferation but induces their apoptosis as well. Turk Jem 2013; 17: 5-7
Key words: Vitamin D, immune system, t cell, 1,25101-112D3, dendritic cell
Son yillarda, vitamin D'nin immun sistemdeki duzenleyici rolu uzerinde durulmaktadir. Vitamin D'nin aktif formu olan 1,25 dihydroxy vitamin D (1,25(OH)2D3), T helper (Th)1 hucrelerinin cogalmasini baskilar ve bu hucrelerden sitokin (interferon (IEN)[gamma], interleukin (IL)-2) uretimini azaltir. Th2 hucrelerinden ise IL-4 ve inflamatuar T hucre aktivitesini baskilayan transforming growth factor uretimini arttirir. Vitamin D uyarisi olmadiginda T hucrelerinde, Th1 fenotipi baskindir. 1,25(OH)2D3 major histokompabilite antijen-II (MHC-II) expresyonuna yol acan dendritik hucrelerin (DC) farklilasmasini, olgunlasmasini ve IL-12 sentezini baskilar, IL-10 sentezini ise arttirir, DC lerin apoptozisini indukler. Boylece 1,25(OH)2D3 DC'e bagli T hucre aktivasyonunu inhibe etmis olur. Invitro olarak 1,25(OH)2D3'un bakterilerin makrofajlar tarafindan uldurulmesini uyardigi diger taraftan makrofallarin ve DClerin anti jen sunma kapasitelerini baskiladigi gusterilmistir. Ayrica Chen ve arkadaslari vitamin D'nin antikor uretiminin duzenlenmesinde de rol oynayabilecegini ileri surmus, calilsmalarinda 1,25(OH)2D3'un B hucrelerinin cogalmasini baskilamakla kalmayip, ayni zamanda B hucrelerinin apoptozunu indukledigini de gostermiVir. Turk Jem 2013; 17: 5-7
Anahtar kelimeler: Vitamin D, immun sistem, T hucreleri, 1,25(OH)2D3, dendritic hucreler
The best characterized effect of vitamin D is on the small intestine and the bone. In the small intestine, vitamin D increases the absorption of calcium by increasing the expression of a specific calcium channel. In bone, vitamin D induces the differentiation of pre-osteoclasts into mature osteoclasts, ultimately promoting removal of calcium and phosphorus from the bone (1-3).
Vitamin D enters the human body via two sources- exposure of the skin to sunlight and diet 111. Solar radiation in the UVB waveband (wavelength, 290 to 315 nm) converts 7-dehydrocholesterol to previtamin D3 which is converted to vitamin D3 (1-5).
Natural dietary sources of vitamin D are wild fresh salmon 1800 IU of D3 per 3.5 oz), cod liver oil 1700 IU of D3 per 1 tps), sun-dried Shiitake mushrooms (1600 IU of D2 per 3.5 oz), fortified foods such as milk (100 IU of D3 per 8 ox), and other supplements Vitamin D2 is produced through the ultraviolet irradiation of ergostero), and vitamin D3 is produced through the ultraviolet irradiation of 7-dehydrocholesterol. Both of those vitamin D forms are used as vitamin D supplements (5).
Vitamin D made in the skin (D31 or ingested (either D2 or D3) travels in the bloodstream bounds to vitamin D-binding protein, and reaches the liver where it is converted to 25-hydroxyvitamin D3 (2510H)D31. This is the major circulating form of vitamin D, the one measured by clinical laboratories to determine the vitamin D status. A normal level of circulating 25(0H)D3 is between 20 and 80 ng/mL. Levels below 20 ng/ml are considered indicative of vitamin D deficiency. Vitamin 2510H1D3 is biologically inactive and must be converted in the kidneys to the biologically active form, 1,25 dihydroxy vitamin D (1,25(0H12D31 (5).
Until 1980, vitamin D has not been imagined to have a role in the functioning of the immune system (6).
The discovery of vitamin D receptor (VDR) in lymphocytes, promyelocytes, macrophages, dendritic cells (DC) and islet cells of pancreas resulted in the idea that vitamin D had functions beyond calcium and phosphorus metabolism and that idea prompted investigations into noncalcemic actions of the vitamin D hormone (6,7).
It has been shown that vitamin D has an important role in the regulation of the immune system. 1,25dihydroxyvitamin D3 11,25 (OH)203) has been determined to suppress the development of autoimmune diseases. However, it does not have any effect on immunity to infectious organisms and other immune system mediated-diseases such as experimental asthma (7). Dendritic cells, T helper 1(Th1) and Th2 cells are direct targets of 1,25(0H)2D3 (8). VDR is not found in appreciable amounts in the B lymphocyte, but in significant concentrations in the T lymphocytes and macrophages 16,91. However, its highest concentration is in the immature immune cells of the thymus and the mature CD8 T lymphocytes. Immune cells are able to synthesize and secrete 1,25(OH)2D3 as they contain 1[alpha]-hydroxylase enzyme, which is necessary for the final activation step in the conversion of vitamin D3 to the biological active form (10). The 1[alpha]-hydroxylase enzyme in immune cells is identical to the renal enzyme, but regulation of its expression and activity is different. Whereas the renal enzyme is principally under the control of calcaemic and bone signals (such as parathyroid hormone and 1,25(OH)2D3, itself), the 1[alpha]-hydroxylase enzyme in the macrophage is primarily regulated by immune signals, interferon [gamma] (IFN-[gamma]) and toll-like receptor agonist which is the powerful stimulator of that enzyme (10). Many studies have shown that some autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis, type 1 diabetes, and inflammatory bowel disease (IBD) can be not only prevented but also suppressed by 1.25(0H)2D3 (a Recent studies have shown significant association of vitamin D deficiency with obesity, type 2 diabetes mellitus and and Hashimoto's thyroiditis (11-25).
Th1 cells secrete IFN-[gamma], interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-[alpha]) and Th2 cells secrete IL-4 and IL-5. All of those cytokines are important for strong antibody-mediated immunity. Activation of Th1 cells is needed for cell-mediated immunity such as host responses to intracellular pathogens and tumors. Th1 cells are misdirected against self proteins in autoimmune diseases such as type 1 diabetes mellitus. Th2 cells are essential in immune responses to extracellular pathogens such as bacteria and parasites. Dendritic cells, Thl and Th2 cells are direct targets of 1,2510H12D3. Normally, expression of VDRs on quiescent CD4+ T cells is very low, but increases 5-fold after the activations of T cells (7,26). 1,25(OH)2D3 reduces the proliferation of purified Thl cells and the productions of IFN[gamma], IL-2, IL-5 and TNF-[alpha]. but, induces IL-4, and transforming growth factor (TGFB) synthesis, which is able to suppress inflammatory T cell activity in Th2 cells (7,26). One of the evidences of that, a murine model of the human disease multiple sclerosis cannot be suppressed by 1,25(OH)2D3 in IL-4-deficient mice (11). The effects of 1,25(0H)2D3 on inhibition of the autoimmune diseases invivo has been shown to depend on IL-2 (27) and (L-4 secretions (28). 1,25(OH)2D3 decreases Thl cell cytokines, but increases secretion of IL-4 which is one of the Th2 cell cytokines. When vitamin D signaling is absent, Thl phenotype is the strongest phenotype in T cell compartment (7). Furthermore, Abe et al. and Tanaka et al. determined that vitamin D can not only inhibit promyelocytes proliferation, but induces their differentiation into monocytes as well (6,29,30).
Vitamin D or VDR deficient hosts have high Th1 cell cytokine levels, although they have low levels of Th2 cell cytokines. When vitamin D signaling is absent, IBDs are more serious and asthma which is driven by Th2 cells does not develop. Results of recent studies suggest a model in which 1.25(OH)2D3 treatment for autoimmune diseases results in inhibition of Th1 cells proliferations and cytokine productions but induction of Th2 cells and Th2 cells cytokine synthesis (7,31). Moreover, 1.25(0H)2D3 inhibits DC differentiation and maturation, leading to down-regulated expression of MHC-II, co-stimulatory molecules and IL-12 and, enhances IL-10 production and promotes DC apoptosis. Because of those effects, 1,25(0H)2D3 inhibits DC-dependent T cell activation 1321. In vitro, it has been determined that 1.25(0H)2D3 stimulates the phagocylosis and killing of bacteria by macrophages but suppresses the antigen presenting ability of those cells and DCs 133,341. IL-12 is produced by macrophages and DCs and is the major determinant of the direction in which the immune system will be activated, since it stimulates the development of CD4 Th1 cells and inhibits the development of Th2 cells. Inhibition of production of IL-12 by vitamin D invitro and a shift from Th1 to Th2 predominance can also be observed after in vivo administration of 1.25(OH)2D3 (35,36).
VDR is not found in appreciable amounts in the B lymphocyte. However, Chen et al. 1371 have suggested that vitamin D might play a role in regulating antibody production. They have found that 1.25(0H)2D3 not only inhibits activated B cells proliferations but induces their apoptosis as well.
In conclusion, vitamin D stimulates the phagocytosis and killing of bacteria by macrophages, but suppresses Thl cell activation by inhibiting the antigen presenting capacity of macrophages and DCs. At the second stage, vitamin D inhibits the secretion of Th1 cytokines and increases IL-4 secretion of Th2 cell. Moreover, vitamin D is suggested to have effects on B lymphocytes proliferation, apoptosis and antibody production.
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Gonca Tamer, Banu Mesci *
Medeniyet University Goztepe, Education and Agencies Hospital, Endocrinology and Metabolism Unit, Istanbul, Turkey
* Medeniyet University GOztepe, Education and Agencies Hospital, Internal Medicine, Istanbul, Turkey
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|Title Annotation:||Review Derleme|
|Author:||Tamer, Gonca; Mesci, Banu|
|Publication:||Turkish Journal of Endocrinology and Metabolism|
|Date:||Mar 1, 2013|
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