Vitamin D upregulates the macrophage complement receptor immunoglobulin in innate immunity to microbial pathogens

AbstractVitamin D deficiency remains a global concern. This ‘sunshine’ vitamin is converted through a multistep process to active 1,25-dihydroxyvitamin D3 (1,25D), the final step of which can occur in macrophages. Here we demonstrate a role for vitamin D in innate immunity. The expression of the complement receptor immunoglobulin (CRIg), which plays an important role in innate immunity, is upregulated by 1,25D in human macrophages. Monocytes cultured in 1,25D differentiated into macrophages displaying increased CRIg mRNA, protein and cell surface expression but not in classical complement receptors, CR3 and CR4. This was associated with increases in phagocytosis of complement opsonised Staphylococcus aureus and Candida albicans. Treating macrophages with 1,25D for 24 h also increases CRIg expression. While treating macrophages with 25-hydroxyvitamin D3 does not increase CRIg expression, added together with the toll like receptor 2 agonist, triacylated lipopeptide, Pam3CSK4, which promotes the conversion of 25-hydroxyvitamin D3 to 1,25D, leads to an increase in CRIg expression and increases in CYP27B1 mRNA. These findings suggest that macrophages harbour a vitamin D-primed innate defence mechanism, involving CRIg.

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Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

Endocrine Reviews ◽

10.1210/er.2016-1070 ◽

2016 ◽

Vol 37 (5) ◽

pp. 521-547 ◽

Cited By ~ 97

Author(s):

Peter J. Tebben ◽

Ravinder J. Singh ◽

Rajiv Kumar

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Active Form ◽

Elevated Serum ◽

Diagnosis And Treatment ◽

Vitamin D Metabolites ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Stone Formers ◽

25 Hydroxyvitamin D

AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

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Responses of serum calcium and phosphorus in the frog Rana tigrina to injection of various vitamin D analogs

Canadian Journal of Zoology ◽

10.1139/z87-323 ◽

1987 ◽

Vol 65 (8) ◽

pp. 2111-2112 ◽

Cited By ~ 4

Author(s):

Ajai K. Srivastav ◽

L. Rani ◽

K. Swarup

Keyword(s):

Vitamin D ◽

Serum Calcium ◽

Vitamin D Analogs ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Rana Tigrina ◽

Calcium Deposits ◽

25 Hydroxyvitamin D ◽

Calcium And Phosphorus

Intraperitoneal injections of either vitamin D3 (4 IU/100 g body wt.), 25 hydroxyvitamin D3 (100 ng/100 g body wt.), or 1,25 dihydroxyvitamin D3 (100 ng/100 g body wt.) for 15 days induced hypercalcemia, hyperphosphatemia, and depletion of calcium deposits in the paravertebral lime sacs in an anuran, Rana tigrina.

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Regulation of vitamin D-1alpha-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney

Journal of Endocrinology ◽

10.1677/joe.0.1640339 ◽

2000 ◽

Vol 164 (3) ◽

pp. 339-348 ◽

Cited By ~ 55

Author(s):

N Akeno ◽

A Matsunuma ◽

T Maeda ◽

T Kawane ◽

N Horiuchi

Keyword(s):

Vitamin D ◽

Enzyme Activity ◽

Mrna Expression ◽

Direct Action ◽

Plasma Concentrations ◽

Mrna Abundance ◽

Subcutaneous Injections ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

25 Hydroxyvitamin D

We investigated the effects of dexamethasone on vitamin D-1alpha-hydroxylase and -24-hydroxylase expression and on vitamin D receptor (VDR) content in the kidneys of mice fed either a normal (NCD) diet or a calcium- and vitamin D-deficient (LCD) diet for 2 weeks. For the last 5 days mice received either vehicle or dexamethasone (2 mg/kg per day s.c.). Dexamethasone significantly increased plasma calcium concentrations without changing plasma concentrations of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) in both NCD and LCD groups. Northern blot and enzyme activity analyses in NCD mice revealed that dexamethasone increased renal VDR mRNA expression modestly and greatly increased 24-hydroxylase mRNA abundance and enzyme activity, but did not affect 1alpha-hydroxylase mRNA abundance and enzyme activity. In mice fed an LCD diet, dexamethasone increased renal VDR mRNA expression 1.5-fold, decreased 1alpha-hydroxylase mRNA abundance (52%) and activity (34%), and markedly increased 24-hydroxylase mRNA abundance (16-fold) and enzyme activity (9-fold). Dexamethasone treatment did not alter functional VDR number (B(max) 125-141 fmol/mg protein) or ligand affinity (K(d) 0.13-0.10 nM) in LCD mice. Subcutaneous injections of 1,25(OH)(2)D(3) (0.24 nmol/kg per day for 5 days) into NCD mice strongly increased renal 24-hydroxylase mRNA abundance and enzyme activity, while there was no effect of dexamethasone on renal 24-hydroxylase expression in these mice. This may be due to overwhelming induction of 24-hydroxylase by 1,25(OH)(2)D(3). These findings suggest that glucocorticoid-induced osteoporosis is caused by direct action of the steroids on bone, and the regulatory effect of glucocorticoids on renal 25-hydroxyvitamin D(3) metabolism may be less implicated in the initiation and progression of the disease.

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Cyclosporin a and Vitamin D Metabolism: Studies in Patients with Psoriasis and in Rats

Clinical Science ◽

10.1042/cs0860627 ◽

1994 ◽

Vol 86 (5) ◽

pp. 627-632 ◽

Cited By ~ 3

Author(s):

A. J. Shaw ◽

M. E. Hayes ◽

M. Davies ◽

B. D. Edwards ◽

F. W. Ballardie ◽

...

Keyword(s):

Vitamin D ◽

Synovial Fluid ◽

Cyclosporin A ◽

Severity Index ◽

Hydroxylase Activity ◽

Local Synthesis ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

25 Hydroxyvitamin D

1. Cyclosporin A, an immunosuppressive drug used to treat psoriasis, stimulates renal synthesis of 1,25-dihydroxyvitamin D in rats. 1,25-Dihydroxy vitamin D can also reduce the activity of psoriasis, and in the present study we have examined the possibility that cyclosporin A mediates some of its actions in psoriasis by renal or extra-renal production of 1,25-dihydroxyvitamin D. 2. Treatment of 12 psoriatic patients with cyclosporin A (5 mg day−1 kg−1) for 3 months significantly improved the psoriasis activity and severity index and reduced glomerular filtration rate, but serum 1,25-dihydroxyvitamin D levels were not changed. However, 1–3 months after stopping cyclosporin A treatment, an increase in the psoriasis activity and severity index score was accompanied by a small, but significant, increase in serum 1,25-dihydroxyvitamin D concentration. Plasma 1,25-dihydroxyvitamin D levels in rats gavaged with cyclosporin A (15 mg day−1 kg−1 for 2 weeks) were significantly increased compared with controls, but a lower dose of cyclosporin A (2.4 mg day−1 kg−1) had no effect. Renal 25-hydroxyvitamin D-24-hydroxylase activity in rat kidney homogenates was not different between control and cyclosporin A-treated rats. Renal 25-hydroxyvitamin D-1α-hydroxylase activity was not detectable in these homogenates. Extra-renal production of 1,25-dihydroxyvitamin D by activated macrophages isolated from the synovial fluid of patients with inflammatory arthritis was reduced after incubation with cyclosporin A (0.1–10 μmol/l) for 30 h or 5 days. 3. It is unlikely that alteration of circulating 1,25-dihydroxyvitamin D concentration is one of the modes of action of cyclosporin A in psoriasis. Since cyclosporin A inhibits 1,25-dihydroxyvitamin D production by activated synovial fluid macrophages, it is unlikely that cyclosporin A mediates some of its therapeutic actions by local synthesis of 1,25-dihydroxyvitamin D within the psoriatic lesion.

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Vitamin D and Calcitonin Treatment in Patients with Femoral Neck Fracture: A Prospective Controlled Clinical Study

Journal of International Medical Research ◽

10.1177/030006058901700305 ◽

1989 ◽

Vol 17 (3) ◽

pp. 226-242 ◽

Cited By ~ 9

Author(s):

E. Harju ◽

R. Punnonen ◽

R. Tuimala ◽

J. Salmi ◽

I. Paronen

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Serum Levels ◽

Serum Calcitonin ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Age Related ◽

Neck Fracture ◽

25 Hydroxyvitamin D

The effects on general and bone metabolism of femoral neck fracture patients of 0.25 μg α-calcoid given orally twice daily ( n=9) and 25 μg calcitonin given subcutaneously 30 times ( n=10) in 10 weeks were studied against a control ( n=ll). Bone histology and histomorphometry showed non-age related osteoporosis in 30% and osteomalacia in 22% of the patients studied. Impaired serum vitamin D status was found in 47 – 88% of patients, secondary hyperparathyroidism and increased serum parathyroid hormone in 59% and decreased serum calcitonin levels in 69%. On histology, normal findings and non-age related osteoporosis on histology were associated with low serum levels of 25-hydroxyvitamin D3,1,25- and 24,25-dihydroxy vitamin D3. Very high serum levels of 1,25-dihydroxyvitamin D3 and low levels of 25-hydroxyvitamin D3 occurred in fracture patients with osteomalacia. Calcitonin improved calcium balance, reduced osteoporosis and increased the serum 1,25- and 24,25-dihydroxyvitamin D3 levels but had no effect on osteomalacia. Vitamin D reduced osteomalacia, slightly increased the serum 1,25-dihydroxyvitamin D3 concentration and decreased serum levels of parathyroid hormone. Both treatments gave a similar slight decrease in serum calcitonin concentrations. A mechanism of action for the treatments is suggested.

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The Role of the Intraplaque Vitamin D System in Atherogenesis

Scientifica ◽

10.1155/2013/620504 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Federico Carbone ◽

Fabrizio Montecucco

Keyword(s):

Vitamin D ◽

Clinical Findings ◽

Peripheral Tissues ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Mouse Tissues ◽

Calcium Phosphorus ◽

25 Hydroxyvitamin D ◽

Physiological Pathways

Vitamin D has been shown to play critical activities in several physiological pathways not involving the calcium/phosphorus homeostasis. The ubiquitous distribution of the vitamin D receptor that is expressed in a variety of human and mouse tissues has strongly supported research on these “nonclassical” activities of vitamin D. On the other hand, the recent discovery of the expression also for vitamin D-related enzymes (such as 25-hydroxyvitamin D-1α-hydroxylase and the catabolic enzyme 1,25-dihydroxyvitamin D-24-hydroxylase) in several tissues suggested that the vitamin D system is more complex than previously shown and it may act within tissues through autocrine and paracrine pathways. This updated model of vitamin D axis within peripheral tissues has been particularly investigated in atherosclerotic pathophysiology. This review aims at updating the role of the local vitamin D within atherosclerotic plaques, providing an overview of both intracellular mechanisms and cell-to-cell interactions. In addition, clinical findings about the potential causal relationship between vitamin D deficiency and atherogenesis will be analysed and discussed.

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1α-Hydroxyvitamin D3 Treatment of Three Patients With 1,25-Dihydroxyvitamin D-Receptor-Defect Rickets and Alopecia

PEDIATRICS ◽

10.1542/peds.80.1.97 ◽

1987 ◽

Vol 80 (1) ◽

pp. 97-101

Author(s):

E. Takeda ◽

Y. Kuroda ◽

T. Saijo ◽

E. Naito ◽

H. Kobashi ◽

...

Keyword(s):

Vitamin D ◽

Calcium Lactate ◽

Type Ii ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

25 Hydroxyvitamin D

Three patients with clinically different severities of vitamin D-dependent rickets, type II, with alopecia, which is 1,25-dihydroxyvitamin D-receptor-defect rickets and is particularly resistant to treatment with calciferol analogues, were treated with large doses of lα-hydroxyvitamin D3 (1α-(OH)D3) and 2 g of calcium lactate. Except for the alopecia, all of the abnormalities of patients 1 and 2 were reversed by treatment with 3 µg/kg/d of 1α-(OH)D3, and those of patient 3, who had the severest manifestations, were reversed by treatment with 6 µg/kg/d. The serum 24,25-dihydroxyvitamin D concentrations of the three patients were low before treatment and those of patients 1 and 2 increased during treatment. These findings suggest that in patients 1 and 2, 25-hydroxyvitamin D-24-hydroxylase was stimulated via a 1,25-dihydroxyvitamin D-receptor-mediated system by treatment with 1α-(OH)D3.

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Calcium, Vitamin D and Parathyroid Hormone Relationships in Pregnant Caucasian and Asian Women and Their Neonates

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328702400103 ◽

1987 ◽

Vol 24 (1) ◽

pp. 22-28 ◽

Cited By ~ 47

Author(s):

F Okonofua ◽

R K Menon ◽

S Houlder ◽

M Thomas ◽

D Robinson ◽

...

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Inverse Correlation ◽

Plasma Calcium ◽

Asian Women ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

The Face ◽

25 Hydroxyvitamin D ◽

Caucasian Women

Plasma calcium, serum 25 hydroxyvitamin D [25(OH)D], 1,25 dihydroxyvitamin D[1,25(OH)2D] and parathyroid hormone (PTH) have been measured in pregnant and newborn Caucasians and Asians. Calcium and 25(OH)D concentrations were lower in Caucasian than in Asian women at all four stages (three trimesters and during labour) of pregnancy. PTH concentrations were greater in Asian than in Caucasian women during the three trimesters, but not at labour, and increased in both groups through pregnancy, without a concomitant change in plasma calcium concentrations. There was a significant inverse correlation between calcium and PTH, as well as 25(OH)D and PTH, concentrations. These data demonstrate the presence of progressive ‘hyperparathyroidism’ during pregnancy in Caucasian and Asian women. The higher PTH concentrations in Asian women may reflect the necessity of maintaining adequate plasma calcium concentrations through PTH-induced osteolysis in the face of vitamin D deficiency. Relative hyperparathyroidism in Asians may contribute to net loss of calcium from the skeleton and osteopenia in Asian women. Calcium, 25(OH)D and l,25(OH)2D concentrations were lower, and those of PTH higher, in Asian newborns compared with Caucasian newborns. Serum 1,25(OH)2D concentrations in the Asian newborn, though lower than respective maternal levels, were comparable with normal adult levels, indicating that 1,25(OH)2D biosynthesis is stimulated in the Asian newborn to compensate for the low serum 25(OH)D concentrations.

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Simultaneous determination of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D in plasma or serum.

Clinical Chemistry ◽

10.1093/clinchem/27.10.1757 ◽

1981 ◽

Vol 27 (10) ◽

pp. 1757-1760 ◽

Cited By ~ 17

Author(s):

M J Jongen ◽

W J van der Vijgh ◽

H J Willems ◽

J C Netelenbos ◽

P Lips

Keyword(s):

Vitamin D ◽

Vitamin D Metabolites ◽

Binding Assays ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Extraction And Purification ◽

Chromatographic Procedure ◽

25 Hydroxyvitamin D ◽

Liquid Chromatographic

Abstract We describe a simultaneous assay for the principal vitamin D metabolites: 25-hydroxyvitamin D, 24-25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D. Special attention has been paid to simplification of the extensive extraction and purification procedures used in previously described simultaneous assays. All three metabolites were isolated with a single extraction step, followed by only one gradient liquid-chromatographic procedure. For final quantitation we used competitive protein binding assays, involving readily available binding proteins and commercially purchased tritiated vitamin D metabolites. Concentrations in the plasma of healthy subjects (mean age, 27 years), sampled during December were 51 (SD 17) nmol/L, 4.1 (SD 1.3) nmol/L, and 124 (SD 26) pmol/L for 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D, respectively. Intra- and interassay CVs for the three metabolites were 4.4 and 3.9%, 6.7 and 8.0%, and 7.0 and 4.8%, respectively.

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Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications

BMC Endocrine Disorders ◽

10.1186/s12902-020-00641-1 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Lina H. M. Ahmed ◽

Alexandra E. Butler ◽

Soha R. Dargham ◽

Aishah Latif ◽

Omar M. Chidiac ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Diabetic Complications ◽

Cross Sectional Study ◽

Cross Sectional ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Metabolite Ratio ◽

25 Hydroxyvitamin D ◽

Artery Disease

Abstract Background Vitamin D deficiency is diagnosed by total serum 25-hydroxyvitamin D (25(OH)D) concentration and is associated with poor health and increased mortality; however, some populations have low 25(OH) D concentrations without manifestations of vitamin D deficiency. The Vitamin D Metabolite Ratio (VMR) has been suggested as a superior indicator of vitamin D status. Therefore, VMR was determined in a population with type 2 diabetes at high risk for vitamin D deficiency and correlated with diabetic complications. Research design and methods Four hundred sisty patients with type 2 diabetes (T2D) were recruited, all were vitamin D3 supplement naive. Plasma concentration of 25-hydroxyvitamin D3 (25(OH)D3) and its metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and its epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), were measured by LC-MS/MS analysis. VMR-1 was calculated as a ratio of 24,25(OH)2D3:25(OH)D3; VMR-2 as a ratio of 1,25(OH)2D3:25(OH)D3; VMR-3 was calculated as a ratio of 3-epi-25(OH)D3: 25(OH)D3. Results An association means that there were significant differences between the ratios found for those with versus those without the various diabetic complications studied. VMR-1 was associated with diabetic retinopathy (p = 0.001) and peripheral artery disease (p = 0.012); VMR-2 associated with hypertension (p < 0.001), dyslipidemia (p < 0.001), diabetic retinopathy (p < 0.001), diabetic neuropathy (p < 0.001), coronary artery disease (p = 0.001) and stroke (p < 0.05). VMR-3 associated with hypertension (p < 0.05), dyslipidemia (p < 0.001) and coronary artery disease (p < 0.05). Conclusions In this cross sectional study, whilst not causal, VMR-2 was shown to be the superior predictor of diabetic and cardiovascular complications though not demonstrative of causality in this cross-sectional study population over VMR-1, VMR-3 and the individual vitamin D concentration measurements; VMR-2 associated with both microvascular and cardiovascular indices and therefore may have utility in predicting the development of diabetic complications.

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