calcitriol and Tuberculosis

Topics: Humans; Tuberculosis; Vitamin D

A variety of abnormalities in vitamin D metabolism have been reported in patients with active tuberculosis. However, intervention trials have produced inconsistent results. We hypothesized that genetic and epigenetic changes in the key genes of the vitamin D metabolic pathway may partly explain the differences between studies.. We performed a case-control study followed by a prospective cohort study. We recruited 122 patients with pulmonary tuberculosis and 118 healthy controls. The serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were measured. The methylation of the promoter regions of key genes in the vitamin D metabolic pathway (CYP24A1, CYP27A1, CYP27B1, CYP2R1, and VDR) was detected using the Illumina MiSeq platform. The specific methylation profiles were examined as epigenetic biomarkers. The sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to estimate the predictive value of the biomarkers.. The baseline serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations in the cases were significantly lower than those in the controls (51.60 ± 27.25 nmol/L vs. 117.50 ± 75.50 nmol/L, Z = - 8.515, P < 0.001; 82.63 ± 51.43 pmol/L vs. 94.02 ± 49.26 pmol/L, Z = - 2.165, P = 0.03). We sequenced 310 CpG sites in five candidate genes. After Bonferroni correction, there were 55 differentially methylated CpG sites between cases and controls; 41.5% were in the CYP27B1 gene, 31.7% were in the CYP24A1 gene, 14.7% were in the VDR gene, and 12.3% were in the CYP27A1 gene. When we designated the CpG sites that remained significant after the Bonferroni correction as the biomarkers, the area under the curve (AUC) for the cumulative methylation was 0.810 (95% CI 0.754-0.866). There was an interaction between CYP27A1 methylation level and 1,25-dihydroxyvitamin D concentration associated with the risk of TB (OR. Both serum vitamin D concentrations and the methylation levels of key genes in the vitamin D metabolic pathway are related to the risk and prognosis of tuberculosis.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Adult; Aged; Case-Control Studies; Cholestanetriol 26-Monooxygenase; DNA Methylation; Epigenesis, Genetic; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Metabolic Networks and Pathways; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Promoter Regions, Genetic; Prospective Studies; Receptors, Calcitriol; ROC Curve; Sequence Analysis, DNA; Tuberculosis; Vitamin D; Vitamin D3 24-Hydroxylase

A uremic patient developed hypercalcemia after tuberculosis infection, and his ionized calcium levels correlated with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) levels. We performed further studies to determine whether monocytes are alternative sites of 1,25(OH)2D3 conversion beyond renal tubular cells. Using an ex vivo bioassay, in this study, we found that 1- α hydroxylase (CYP27B1) activity in monocytes is significantly higher in patients with active tuberculosis (TB) than in those with frequent TB contact. However, when monocytes from patients with active TB were restimulated with antigen derived from Mycobacterium tuberculosis, less 1,25(OH)2D3 was observed. In contrast, the level of 1,25(OH)2D3 was unchanged in those with frequent TB contact. We conclude that monocytes may be an alternative source of 1- α hydroxylase that could convert 25-hydroxyvitamin D3 to the more active 1,25(OH)2D3.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Adult; Calcium; Enzyme Activation; Female; Humans; Male; Middle Aged; Monocytes; Tuberculosis; Uremia; Vitamin D

Matrix metalloproteinases (MMP) can degrade all components of pulmonary extracellular matrix. Mycobacterium tuberculosis induces production of a number of these enzymes by human macrophages, and these are implicated in the pathogenesis of pulmonary cavitation in tuberculosis. The active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], has previously been reported to inhibit secretion of MMP-9 in human monocytes (MN), but its influence on the secretion and gene expression of MMP and tissue inhibitors of MMP (TIMP) in M. tuberculosis-infected cells has not previously been investigated. We therefore determined the effects of 1alpha,25(OH)(2)D(3) on expression, secretion and activity of a number of MMP and TIMP in M. tuberculosis-infected human leucocytes; we also investigated the effect of 1alpha,25(OH)(2)D(3) on the secretion of interleukin-10 (IL-10) and prostaglandin E(2) (PGE(2)), both transcriptional regulators of MMP expression. We found that M. tuberculosis induced expression of MMP-1, MMP-7 and MMP-10 in MN and MMP-1 and MMP-10 in peripheral blood mononuclear cells (PBMC). 1alpha,25(OH)(2)D(3) significantly attenuated M. tuberculosis-induced increases in expression of MMP-7 and MMP-10, and suppressed secretion of MMP-7 by M. tuberculosis-infected PBMC. MMP-9 gene expression, secretion and activity were significantly inhibited by 1alpha,25(OH)(2)D(3) irrespective of infection. In contrast, the effects of 1alpha,25(OH)(2)D(3) on the expression of TIMP-1, TIMP-2 and TIMP-3 and secretion of TIMP-1 and TIMP-2 were small and variable. 1alpha,25(OH)(2)D(3) also induced secretion of IL-10 and PGE(2) from M. tuberculosis-infected PBMC. These findings represent a novel immunomodulatory role for 1alpha,25(OH)(2)D(3) in M. tuberculosis infection.

Topics: Cells, Cultured; Dinoprostone; Enzyme Activation; Gene Expression Regulation; Humans; Interleukin-10; Leukocytes, Mononuclear; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Protease Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tissue Inhibitor of Metalloproteinases; Tuberculosis; Vitamin D

Topics: Breast Neoplasms; Female; Humans; Multiple Myeloma; Tuberculosis; Vitamin D