International Journal of Epidemiologic Research, 2016; 3(1): 69-85. ijer.skums.ac.ir The role of vitamin D3 and vitamin B9 (Folic acid) in immune system 1 1* 2 3 Reza Mansouri , Maryam Moogooei , Mozhgan Moogooei , Nastaran Razavi , Amir Hossein Mansourabadi1 1Immunology Dept., Shahid Sadoughi University of Medical Sciences, Yazd, I.R. Iran; 2Immunology Dept., Rafsanjan University of Medical Sciences, Rafsanjan, I.R. Iran; 3Research and Technology Deputy, Shahrekord University of Medical Sciences, Shahrekord, I.R. Iran. Received: 1/Nov/2015 Accepted: 27/Dec/2015 ABSTRACT Background and aims: Vitamins are essential constituents of our diet that Longley have been known to influence the immune system. Vitamin D3 and B9 have received particular Review attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. 1, 25(OH)2D3 metabolizing enzymes and vitamin D receptor (VDR) are present in many cell types including various immune cells such as article antigen-presenting-cells, T cells, B cells. Methods: In this mini review, we study 30 novel articles since 2009 to 2015 about the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation, T-helper-cell differentiation and regulation of the immune response. 4+ Results: 1, 25(OH)2D3 has direct effect on CD T (T-helper) cells for suppressing various cytokines such as IFN-γ, IL-17, IL-21 and IL-22, while enhancing the regulatory Tcells. In vitro studies show that Treg cells could be differentiated from naive T cells in vitamin B9-reduced condition. Conclusions: These findings provide a new link between diet and the immune system, which could maintain the immunological homeostasis and clarify the beneficial roles of vitamins in informing the design of vitamin analogs as pharmacologic agents for the generation and maintenance of a healthy immune condition. Keywords: Vitamin D3, Vitamin B9, Immune system, Regulatory T Cell. INTRODUCTION Vitamins are organic compounds that commensal bacteria. Some vitamins (e.g. the host organism cannot synthesize in vitamin B family and vitamin C) are sufficient quantities and that therefore need water-soluble, whereas others (e.g., vitamins to be supplied exogenously by the diet or A, D, E, and K) are hydrophobic. Both *Corresponding author: Maryam Moogooei, Immunology Dept., Shahid Sadoughi University of Medical Sciences, Yazd, I.R. Iran, Tel: 00982188683492, E-mail: [email protected] 69 Mansouri R, et al. The vitamin D3 and vitamin B9 in immune system hydrophilic and hydrophobic vitamins and vitamins and their metabolites in immune their metabolites have diverse functions in responses.3 many biologic events, including Vitamin D is a group of fat soluble immunologic regulation responses is better. vitamins responsible for absorption of than regulation. Indeed, vitamin deficiency calcium and phosphate in the small intestine results in high susceptibility to infection and and stimulates osteoclast differentiation.4 immune diseases.1 Until the mid-1930s, Two major forms of vitamin D exist. when the first commercial yeast-extract Vitamin D2 (ergocalciferol), found in plants, vitamin B complex and semi-synthetic is produced by ultraviolet B irradiation of vitamin C supplement tablets were sold, ergosterol and can be consumed as a vitamins were obtained solely through food supplement or in fortified foods.5 Vitamin intake, and changes in diet (which, for D3 (cholecalciferol) is synthesized in the example, could occur during a particular human epidermis or consumed in the form growing season) usually greatly altered the of natural (for example, fish) or fortified types and amounts of vitamins ingested. food sources or as a supplement.4 Despite its However, vitamins have been produced as name, vitamin D is not really a vitamin, commodity chemicals and made widely it is the precursor to the potent steroid available as inexpensive semisynthetic and hormone calcitriol (also known as synthetic-source multivitamin dietary and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), food supplements and additives, since the which mediates numerous actions in many 6 middle of the 20th century. Thirteen tissues of the body. Cutaneous vitamin D3 vitamins are universally recognized at generated by high energy UVB photons present. Vitamins are classified by their provides 90% of the human vitamin biological and chemical activity, not their requirement. The biological half-life of structure. The largest number of vitamins, 25-OHD3 is 2 months, so this metabolite the B complex vitamins, function as effectively integrates sunlight’s energy precursors for enzyme cofactors, that help signal over time.7 With the finding of the enzymes in their work as catalysts in vitamin D receptor (VDR) in nearly every metabolism.2 In this role, vitamins may be tissue and the more recent discovery of tightly bound to enzymes as part of thousands of VDR binding sites throughout prosthetic groups: For example, biotin is the genome controlling hundreds of genes, part of enzymes involved in making fatty the interest in vitamin D and its impact on acids. They may also be less tightly bound multiple biologic processes has accelerated to enzyme catalysts as coenzymes, tremendously as evidenced by the detachable molecules that function to carry thousands of publications each year for the chemical groups or electrons between past several years.5 molecules. For example, folic acid may In the human skin, cholecalciferol is carry methyl, formyl, and methylene groups synthesized from 7-dihydrocholesterol when in the cell. Although these roles in assisting exposed to UVB. The production of vitamin enzyme-substrate reactions are vitamins' D3 (D3) in the skin is not an enzymatic best-known function, the other vitamin process. Vitamin D3 (cholecalciferol) is functions are equally important. Previously produced through a two-step process in vitamins were thought to regulate the which the B ring is broken by UV light immune system in an indiscriminant (spectrum 280-320 UVB) radiation from the manner, but accumulating evidence has sun, forming pre-D3 that isomerizes to D3 in revealed specific functions of individual a thermosensitive but noncatalytic process.8 70 International Journal of Epidemiologic Research, 2016; 3(1): 69-85. Cholecalciferol is biologically inactive and tissues of the body, including bone, immediately binds to vitamin D binding pancreatic β cells, parathyroid gland, brain, proteins or albumin.9 It then enters the skin, prostate, testes, heart, skeletal muscle circulation and is hydroxylated in the liver, tissue, breast, liver, lung, intestine, kidneys, catalyzed by the enzymes CYP2R1 and adipose cells and immune response cells, CYP27A1, which results in the production such as macrophages, dendritic cells and of the inactive form 25 hydroxy vitamin D activated B- and T-cells.16 It is comprised of (25 (OH)D) which represents the main 3 domains: the N-terminal DNA binding circulating vitamin D metabolite and is the domain with two zinc fingers that bind to the most reliable parameter to define human grooves of the DNA at discrete sites vitamin D status.10 In the kidney, 25 (OH)D (VDREs), the C-terminal ligand binding is further converted to the circulating domain, and the hinge region binding of biologically active compound calcitriol these two domains together. The ligand (1, 25(OH)2D) by the enzyme 1-α- binding domain structure has been solved by hydroxylase (CYP27B1) which is under x-ray crystallography.17 It is comprised of strict control of parathyroid hormone and the 12 helices. The terminal helix serves as a phosphaturic hormone fibroblast growth gating mechanism closing around the factor 23 (FGF-23).11 Calcitriol levels are incorporated ligand and forming an interface tightly regulated in a renal negative for coactivators as well as facilitating the feedback loop, including inhibition of interaction of VDR with its heterodimer CYP27B1 by high levels of calcitriol and partner, generally RXR. Although VDR FGF-23 and stimulation of the enzyme preferentially binds to RXR, creating a CYP24A1 (24-hydroxylase) which VDR-RXR dimer, VDR can also bind other metabolizes calcitriol into the inactive, water receptors of the nuclear receptor soluble form, calcitroic acid, which is then superfamily, which include thyroid, vitamin excreted in the bile.12 Circulating levels of A, PPAR-γ and other orphan receptors.18 calcitriol are mainly determined by renal The VDR-RXR dimer can regulate genes in CYP27B1 activity.13 However, other cell several systems and tissues. Although there types including immune cells, also express is substantial variability in quence of CYP27B1 and are able to convert the VDREs, the most prevalent motif for the inactive, circulating form 25(OH)D into the VDRE sequence consists of two half-sites, active hormone in an autocrine or paracrine each with the six-nucleotide consensus manner. Especially in immune cells, such as sequence, GGTCCA, separated by 3 other macrophages and dendritic cells, a lack of nucleotides of any sequence. This motif is feedback mechanisms compared to kidney known as Direct Repeat 3 (DR3), although cells allows the production of high local other configurations of VDRE-binding sites, concentrations of calcitriol needed for including DR6 and DR4, exist in some immune modulation.14 vitamin D-regulated genes.19 VDR binding Vitamin D receptor (VDR) is a to its VDRE then recruits coregulatory transcription factor and member of the complexes required for its genomic activity. steroid hormone and nuclear hormone These complexes can be both gene and cell receptor family. The VDR was identified in specific, enabling the selectivity of 1969 and its crystal structure was cloned in 1,25(OH)2D action from cell type to cell 1987 and binding to its natural ligand were type. These complexes include a subunit that characterized in 2000.15 Since its discovery, directly binds to the VDR generally through researchers have detected the VDR in many an LXXLL motif along with a number of 71 Mansouri R, et al.