Vitamin D3: research breakthroughs and therapeutic use

Abstract

Vitamin D3 (cholecalciferol), the natural form of vitamin D, is produced in the skin from 7-dehydrocholesterol. The synthesis of vitamin D in the skin is the most important source of vitamin D. Vitamin D can also be taken through nutrition, in the diet, but it is present in only a few food sources, containing relevant levels of vitamin D. 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] is the hormonally active form of vitamin D.  Novel researches show it generates a number of extraskeletal biological responses including inhibition of variety types cancer progression, effects on cardiovascular disorders and mediates a protection against a number of inflammatory, autoimmune and infection diseases The biological actions of 1,25(OH)₂D₃ are mediated by the VDR. The genomic mechanism of 1,25(OH)₂D₃ action involves the direct binding of 1,25(OH)₂D₃ activated VDR/RXR to specific DNA sequences  in and around target genes resulting in either activation or repression of transcription [7] VDR modulates the expression of genes involved in immune function and cytokine production. The VDR and CYP27B1, the enzyme located in kidneys and target organs, are present in immune competent cells, bronchial and pulmonary epithelial cells, among others, and is up-regulated following the ligation of specific toll-like receptors by extracellular pathogens, implicating vitamin D in innate immunity. By binding the VDR, calcitriol induces several endogenous antimicrobial peptides (AMP) in monocytes, neutrophils and epithelial cells including cathelicidin LL-37, α-defensin,β defensing and neutrophil gelatinase-associated lipocalin and up-regulates nitric oxide (NO) synthase. Since the inflammatory response associated with infections such influenza, pneumonia and sepsis increases both clinical severity and mortality, the ability to reduce inflammation may allow vitamin D to decrease mortality and disease burden in certain infections. Notwithstanding the width of possible vitamin D application field, which being known now, large-scale clinical trials are still demanded. Our review has the aim to summarize current scientific understanding of Vitamin D₃ effects on the immunological field with the focus on its capacity to enhance the anti-infection and anti-inflammatory immune reactivity. Vitamin D and Tuberculosis. Vitamin D has been widely studied in the prevention and treatment of tuberculosis. Current studies were focused on how calcitriol enhances the antimicrobial effects of macrophages and monocytes – important effector cells, fighting against pathogens such as Mycobacterium tuberculosis (MBT). Several studies tracked the impact of vitamin D on cytokines that promote anti-MTB activity and the resolution of infection. Suppression of antigen-stimulated pro-inflammatory cytokines, attenuation of anti-inflammatory cytokines, and a more rapid treatment-induced resolution of lymphopenia and monocytosis associated with TB infection occurred following 100,000 IU doses of vitamin D₃ given monthly for 4 months. Conversion of sputum smear or sputum culture was used to measure response to treatment in several studies, though only sputum culture conversion is independently linked to long-term risk of treatment failure and relapse. Also it was found  that 10,000 IU of vitamin D₃ given daily for 6 weeks to significantly increase sputum smear conversion (100 % in the treatment group vs. 76,7 % in the placebo group, p=0,002). IFN-γ levels were impacted variably: 2 doses of vitamin D₃  (600,000 IU)) led to increasing of IFN-γ expression , while a single 100,000 IU dose of vitamin D₂ showed no change .  Negative results in some studies could be explained by variability of the Taq1 vitamin D receptor genotype polymorphism. It was shown that significantly accelerated conversion is appropriate of patients who have a tt genotype compared to those with the Tt or TT genotype. But these results were not confirmed by another study, where were founded no interaction between VDR genotype effectiveness of vitamin D.  Several trials show vitamin D given largely as an adjunctive therapy with traditional anti-tuberculosis regimens in a variety of dose and dosing schedule has some impact on clearance of MBT from sputum in the wide number randomized controlled multicenter trials of patients with active tuberculosis infection. Patients with infection of MBT with different strains of tuberculosis can take benefits from Vitamin D₃ consumption due to its effect on the clearance of MTB from sputum and on dampening the inflammatory response or anthropometric changes that may help tuberculosis patients recover. A significant microbiologic effect of vitamin D₃ was indicated in several trials that, also, sustained by in vitro tests, where its antimycobacterial effects in cultured macrophages was shown. Antimycobacterial effect is provided enhances the expression of the anti-microbial peptide human cathelicidin (hCAP18) in cultured macrophages. The clinical benefit after high vitamin D₃ doses administrating to patients does not depend of their vitamin D₃ marked deficiency. The cause of this variation remains unexplained. The role of genetic polymorphisms in the vitamin D receptor, or in the multiple enzymes involved in its metabolism in vitD₃ effectiveness remains unproved. Measurement of calcitriol-induced antimycobacterial activity in ex vivo whole blood culture in future studies may help in understanding the functional effects of specific genetic polymorphisms. So, big attention will be required in future studies to determine mechanism of vitamin effect on patients with tuberculosis.