The coming of age of 1,25-dihydroxyvitamin D3 analogs as immunomodulatory agents

doi:10.1016/S1471-4914(02)02294-3

Trends in Molecular Medicine

Volume 8, Issue 4, 1 April 2002, Pages 174-179

https://doi.org/10.1016/S1471-4914(02)02294-3 Get rights and content

Abstract

The active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], is a secosteroid hormone that regulates calcium and bone metabolism, controls cell proliferation and differentiation, and exerts immunoregulatory activities. This range of functions has been exploited clinically to treat a variety of conditions, from secondary hyperparathyroidism to osteoporosis, to autoimmune diseases such as psoriasis. Recent advances in understanding 1,25(OH)₂D₃ functions and novel insights into the mechanisms of its immunomodulatory properties suggest a wider applicability of this hormone in the treatment of autoimmune diseases and allograft rejection.

Section snippets

Direct effects of 1,25(OH)₂D₃ and its analogs in T cells

Soon after the discovery of VDR expression in T cells 6, 14, 1,25(OH)₂D₃ was shown to inhibit antigen-induced T-cell proliferation [15] and cytokine production [16]. Later studies demonstrated selective inhibition of Th1 cell development 17, 18, although it was not clarified how much of this effect could be accounted for by modulation of APC functions. Indeed, several key cytokines in T cells are direct targets for 1,25(OH)₂D₃ and its analogs, in particular Th1 cytokines, such as interleukin

Regulatory effects of 1,25(OH)₂D₃ and its analogs in antigen-presenting cells

APCs, and in particular dendritic cells (DCs) are key targets of 1,25(OH)₂D₃ and its analogs, both in vitro and in vivo. Earlier indications for the capacity of 1,25(OH)₂D₃ to target APCs were corroborated by its ability to inhibit the production of IL-12 17, 26, an APC-derived cytokine critical for Th1 cell development. More recent work has demonstrated that 1,25(OH)₂D₃ and its analogs inhibit the differentiation and maturation of DCs 27, 28, 29, 30, a crucial APC in the induction of

Immunomodulatory effects of 1,25(OH)₂D₃ and its analogs in autoimmune diseases and allograft rejection

The immunoregulatory properties of 1,25(OH)₂D₃ and its analogs have been demonstrated in different models of autoimmune diseases and in experimental organ transplantation (Table 1). Notably, 1,25(OH)₂D₃ and its analogs can prevent systemic lupus erythematosus in lpr/lpr mice [37], EAE 18, 38, 39, collagen-induced arthritis 40, 41, Lyme arthritis [41], inflammatory bowel disease [42] and autoimmune diabetes in non-obese diabetic (NOD) mice 43, 44. 1,25(OH)₂D₃ analogs are able not only to prevent

Conclusions

VDR ligands have pleiotropic activities in immune regulation. It is intriguing that several different molecular mechanisms of cytokine inhibition by 1,25(OH)₂D₃ exist. APCs and T cells can be direct targets of the hormone, leading to the inhibition of pathogenic effector T cells and enhancing the frequency of T cells with regulatory properties, largely via induction of tolerogenic DCs. These immunoregulatory activities, coupled with the absence of major side effects once calcemia is under

Glossary

1,25(OH)₂D₃: The di-hydroxylated, biologically active form of vitamin D₃, also known as calcitriol. It is a central hormone in calcium homeostasis and bone metabolism, but has also a number of other functions, and notably powerful immunomodulatory properties.
1,25(OH)₂D₃ analogs: Chemically modified molecules derived from 1,25(OH)₂D₃. Modifications have been made throughout the molecule, to obtain analogs with the desired properties. More than 1000 different vitamin D analogs have been synthesized

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People from some parts of the world traditionally depend on different herbal medicines for fertility regulation. The Mishing women of Assam, India have been using the dry root powder of Persicaria hydropiper for years as a birth control medicine. The present study was designed to investigate the chemical composition of methanolic extract from the dry roots of P. hydropiper as well as to study its anti-implantation effect. P. hydropiper roots were collected from paddy fields and the methanolic extract was prepared using dry powdered roots. Gas chromatography-mass spectrometry (GCMS) analysis of the methanolic root extract was performed for phytochemical analysis. The estrous cycle of the female mice was monitored by observation of the cells in the vaginal smear. The estrogenic and anti-implantation effect was observed using routine histological procedures with Haematoxylin & Eosin staining performed in mice. Total serum cholesterol level was also measured. The GCMS analysis revealed the presence of stigmasterol and 3-deoxyestradiol, which are known to possess antifertility properties. The extract (1000 mg/kg bodyweight dose) altered the duration and sequence of the estrous cycle of cyclic females with a prolonged metestrous of 2 days, followed by an early estrous. There was hyperplasia in the endometrial epithelium and even shedding of the same on high duration treatment on day 6. There was a significant (p < 0.05) rise in total cholesterol levels in the treated groups. The highest rise was observed in the day 1 group (from 67.91 ± 1.98 to 147.53 ± 3.20 mg/dl) while the lowest change was there in the day 2 group (from 78.76 ± 2.04 to 103.26 ± 2.34 mg/dl). The presence of compounds like stigmasterol and 3-deoxyestradiol with profound antifertility properties possibly has an influence on the molecular pathway for embryo implantation. The changes in uterine histoarchitecture in the form of uterine hyperplasia on treatment with the extract point out towards the effect of the estrogenic compounds. Such implantation preventing results provides support to the traditional belief and opens the door for new drug discovery for reproduction regulation. A detailed molecular study is necessary in this regard.
The effects of dietary vitamin D supplementation and in vitro 1,25 dihydroxyvitamin D<inf>3</inf> treatment on autophagy in bone marrow-derived dendritic cells from high-fat diet-induced obese mice
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Obesity is associated with the dysregulation of vitamin D metabolism and altered immune responses in bone marrow-derived dendritic cells (BMDCs). Vitamin D can affect the differentiation, maturation, and activation of dendritic cells (DCs) and regulate autophagy via vitamin D receptor signaling. Autophagy was shown to be involved in the functions of DCs. We investigated the effects of dietary vitamin D supplementation and in vitro 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) treatment on autophagy in BMDCs from control diet (CON)-fed lean and high-fat diet (HFD)-induced obese mice. C57BL/6 male mice were fed CON or HFD with 10% or 45% kcal fat, respectively, supplemented with 1,000 or 10,000 IU vitamin D/kg diet (vDC or vDS) for 12 weeks. BMDCs were generated by culturing bone marrow cells from the mice with 20 ng/mL rmGM-CSF and treated with 1 nM 1,25(OH)₂D₃. Maturation of BMDCs was induced by lipopolysaccharide (50 ng/mL) stimulation. Treatment with 1,25(OH)₂D₃ inhibited the expression of phenotypes related to DC function (MHC class Ⅱ, CD86, CD80) and production of IL-12p70 by BMDCs from control and obese mice, regardless of dietary vitamin D supplementation. LC3Ⅱ/Ⅰ and VPS34 protein levels increased, and p62 expression decreased, after 1,25(OH)₂D₃ treatment of the BMDCs in CON-vDC only. Vdr mRNA levels decreased following 1,25(OH)₂D₃ treatment of BMDCs in the HFD-vDC. In conclusion, autophagy flux was increased by 1,25(OH)₂D₃ treatment of the BMDCs in CON-vDC but not in the HFD-vDC group. This suggests that the decreased expression of Vdr following 1,25(OH)₂D₃ treatment might have affected autophagy flux in BMDCs from obese mice.
Associations of vitamin D receptor rs1544410 polymorphism with type 1 diabetes mellitus risk: Systematic review and meta-analysis
2021, Meta Gene
Inconclusive findings on the association of polymorphisms in vitamin D receptors (VDR) with the risk of type 1 diabetes mellitus (T1DM) have been obtained in several studies.
The present meta-analysis was conducted to comprehensively examine the effects of rs7975232, rs1544410, rs2228570, and rs731236 polymorphisms in the VDR gene on the risk of T1DM in the Eastern Mediterranean Region (EMRO) population.
The PubMed, Scopus, Web of Science, and Google Scholar databases were searched for related literature published up to May 2021. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to measure the strength of the associations. The Newcastle–Ottawa Scale was used to the assessment of the methodological quality of each study. Meta-regression and subgroup analysis were performed to find the potential sources of heterogeneity.
Nine studies consisting of 1618 subjects were included in this study. A protective association for rs1544410 polymorphism under allelic model [OR = 0.597, 95% CI (0.360–0.989), P = 0.045], codominant model [OR = 0.432, 95% CI (0.220–0.851), P = 0.015], and dominant model [OR = 0.460, 95% CI (0.257–0.824), P = 0.009], and a predisposing association under recessive model [OR = 1.607, 95% CI (1.017–2.539), P = 0.042] with T1DM risk was found in selected population. However, no significant associations between rs7975232, rs2228570 and rs731236 and T1DM risk were observed (P > 0.05).
The present meta-analysis suggested that rs1544410 polymorphism might be associated with risk of T1DM in the EMRO population.
Active vitamin D3-glycoside preserves weight gain and modulates the inflammatory response in broiler chickens challenged with lipopolysaccharide
2020, Animal Feed Science and Technology
This study evaluates the effects of dietary supplementation of 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃) glycoside on the performance, tibia mineral concentrations, and inflammatory responses of broilers challenged with lipopolysaccharides (LPS). At 20 days old, 144 male broilers were weighed and distributed in a completely randomized design with three treatments, eight replicates, and six birds per experimental unit. The treatments were a basal diet without LPS administration (CON), a basal diet with LPS administration (CON + LPS), and a basal diet supplemented with 5 μg of 1,25(OH)₂D₃-glycoside/kg of diet with LPS administration (SUP + LPS). The LPS challenge was administered as intraperitoneal applications at 21 and 23 days of age (1 and 1.12 mg/kg of body weight, respectively). Four hours after the first LPS application, one bird per experimental unit was euthanized to collect blood, spleen, duodenum, and jejunum samples. We evaluated the broilers’ performance at 25 days of age, when all birds were slaughtered to analyze calcium and phosphorus levels in the tibia. We analyzed the data using a one-way ANOVA and compared the means with the Tukey test at 0.05 significance. The CON + LPS birds showed less weight gain (WG) than the CON and SUP + LPS groups (P = 0.019). The treatments had no effect on feed intake, feed conversion, serum levels of bone alkaline phosphatase, calcium, and phosphorus, or calcium and phosphorus in the tibia of birds (P > 0.05). The IL-10 level in the jejunum was higher (P = 0.011) in SUP+LPS birds than in the CON and CON+LPS groups. Among birds challenged with LPS, those supplemented with 1,25(OH)₂D₃-glycoside showed greater mRNA expression of IL-10 (P = 0.014) and IL-1β (P = 0.045) in the spleen; however, no effect was observed on the expression of these cytokines in the duodenum and jejunum of the birds (P > 0.05). In conclusion, dietary supplementation with 1,25(OH)₂D₃-glycoside preserves WG and modulates the inflammatory response by increasing the production of IL-10 in the jejunum and the mRNA expression of IL-10 and IL-1β in the spleens of broilers challenged with LPS, although bone mineralization is unaffected.
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Previous studies have suggested that type 2 diabetes mellitus with lower extremity arterial disease is related to 25-hydroxyvitamin D deficiency. The purpose of this study is to explore the relation between vitamin D supplementation and the characteristics of type 2 diabetes mellitus complicated with lower extremity arterial disease.
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Trends in Molecular Medicine

ReviewThe coming of age of 1,25-dihydroxyvitamin D3 analogs as immunomodulatory agents

Abstract

Section snippets

Direct effects of 1,25(OH)2D3 and its analogs in T cells

Regulatory effects of 1,25(OH)2D3 and its analogs in antigen-presenting cells

Immunomodulatory effects of 1,25(OH)2D3 and its analogs in autoimmune diseases and allograft rejection

Conclusions

Glossary

J. Steroid Biochem. Mol. Biol.

Arch. Biochem. Biophys.

Mol. Cell

J. Nutr.

J. Neuroimmunol.

Biochem. Biophys. Res. Commun.

Exp. Hematol.

FEBS Lett.

J. Biol. Chem.

J. Nutr.

J. Nutr.

Hepatology

Transplant. Proc.

Transplant. Proc.

Transpl. Immunol.

Transplant. Proc.

Metabolism

J. Neuroimmunol.

Clin. Immunol. Immunopathol.

Immunomodulatory effects of 1,25-dihydroxyvitamin D3

Curr. Opin. Nephrol. Hypertens.

Vitamin D: its role and uses in immunology

FASEB J.

The nuclear vitamin D receptor: biological and molecular regulatory properties revealed

J. Bone Miner. Res.

Gene regulation by vitamin D3

Crit. Rev. Eukaryot. Gene Expr.

1,25-dihydroxyvitamin D3 receptors in human leukocytes

Science

Dendritic cells from human tissues express receptors for the immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol

Immunology

In vitro and in vivo analysis of the immune system of vitamin D receptor-knock out mice

J. Bone Miner. Res.

Targeted ablation of the 25-hydroxyvitamin D1α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction

Proc. Natl. Acad. Sci. U. S. A.

Vitamin D analogs: mechanism of action and therapeutic applications

Curr. Med. Chem.

Recent developments in the use of vitamin D analogues

Expert Opin. Invest. Drugs

Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation

J. Clin. Endocrinol. Metab.

1,25-Dihydroxyvitamin D3 inhibits antigen-induced T cell activation

J. Immunol.

Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA

J. Clin. Invest.

Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D3

Eur. J. Immunol.

Review
The coming of age of 1,25-dihydroxyvitamin D₃ analogs as immunomodulatory agents

Direct effects of 1,25(OH)₂D₃ and its analogs in T cells

Regulatory effects of 1,25(OH)₂D₃ and its analogs in antigen-presenting cells

Immunomodulatory effects of 1,25(OH)₂D₃ and its analogs in autoimmune diseases and allograft rejection

Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D₃