Non-classical Actions Of Vitamin Research Articles

Role of Active Vitamin D3 in Immunity

ABSTRACT Introduction The active vitamin D3—1,25 dihydroxy cholecalciferol—is the key player in calcium and phosphorus metabolism and skeletal growth and functions. However, recent new developments have revealed its role in other tissues as well, referred to as the nonclassical actions of vitamin D. Not only the endocrinal effects, evidence indicates that vitamin D3 also has autocrine and paracrine functions due to its extrarenal synthesis by many cells, including the immune cells. All cells of the immune system have vitamin D receptors and show wide-ranging effects to it. It impacts both the innate and adaptive immune systems and the overall influence points to anti-infective, anti-inflammatory, immunosuppressive, and regulatory roles. It shows a significant role in chronic inflammatory and autoimmune diseases as well in susceptibility to infections. In this review, newer developments on the role of vitamin D in immunity and the underlying mechanism are discussed with possible future reflections. How to cite this article Verma R, Singh S, Singh B, Goswami B, Gupta SK. Role of Active Vitamin D3 in Immunity. Indian J Med Biochem 2017;21(2):166-175.

Abstract A49: Meta-analysis of vitamin D-binding protein and cancer risk

Abstract Antiproliferative effects of 1,25-dihydroxyvitamin D, the biologically active form of vitamin D, are well established in various cell types, including normal and malignant cells, by influencing cell differentiation, cell growth and apoptosis. In addition meta-analyses of epidemiological studies showed that serum 25-hydroxyvitamin D (25OHD) and vitamin D receptors polymorphisms (VDRs) are associated with cancer risk. The biological effects of vitamin D are mediated by an abundance of the vitamin D binding protein (DBP) and VDRs. The gene for the vitamin D–binding protein, known as ‘‘group-specific component’’ (Gc), is also a logical candidate in the vitamin D pathway because its major function is to transport vitamin D metabolites in the blood to different target organs. Variants in this gene have been shown to alter plasma concentrations of 25OHD and several studies investigated Gc SNPs and DBP in association with cancer risk with controversial results. Thus we carried out a comprehensive literature search and meta-analysis to investigate these associations. A systematic literature search was performed following a pre-defined protocol and using validated search strategies up to April 2014. We included for 24 independent studies for a total of 38,331 cases and 25,050 controls, from several countries Australia, Canada and USA, Finland, Germany, the Netherlands, Spain, UK, China and Iran. Data collected concern the following cancer sites: skin (n. of estimates=1), bladder (n=2), breast (n=3), colon-rectum (n=5), endometrium (n=1), liver (n=1), esophagus (n=1), stomach (n=1), melanoma (n= 3), pancreas (n= 2), prostate (n= 5) and kidney (n=1). Through random effect models we calculated the Summary Odd Ratios (SORs) for serum DBP (n. of estimates=6) and the following polymorphisms: rs2282679 (n. of estimates=7), rs12512631 (n=4), rs7041 (n=17), rs4588 (n=12), rs1155563 (n=5) and rs1352844 (n=3). We found a significant 8% increase cancer risk at any site for rs4588 variant (dominant model) and a non significant decrease risk at increasing level of DBP: SOR= 0.94 (0.86-1.02) per an increase of 1000 nmol/L. We evaluated also departure from Hardy-Weinberg equilibrium (HWE) in controls and sensitivity analyses excluding studies that do not respect HWE did not show important changes in results. No indication of publication bias was found. In conclusion we found some interesting associations indicating a possible role of DBP in cancer etiology. Further studies should consider also the role of the ‘free’ unbound part of 25OHD, that drives many of the non-classical actions of vitamin D, and it is dependent on the concentration of DBP.

Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D.

Non-classical actions of vitamin D were first suggested over 30 years ago when receptors for the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), were detected in various tissues and cells that are not associated with the regulation of calcium homeostasis, including activated human inflammatory cells. The question that remained was the biological significance of the presence of vitamin D receptors in the different tissues and cells and, with regard to the immune system, whether or not vitamin D plays a role in the normal immune response and in modifying immune mediated diseases. In this article findings indicating that vitamin D is a key factor regulating both innate and adaptive immunity are reviewed with a focus on the molecular mechanisms involved. In addition, the physiological significance of vitamin D action, as suggested by in vivo studies in mouse models is discussed. Together, the findings indicate the importance of 1,25(OH)2D3 as a regulator of key components of the immune system. An understanding of the mechanisms involved will lead to potential therapeutic applications for the treatment of immune mediated diseases.

Vitamin D Insufficiency and Asthma Severity in Adults From Costa Rica

PurposeNon-classical actions of vitamin D as a cytokine are related to the immunopathology of asthma. Few studies have examined vitamin D levels and asthma severity in adults. The aim of this research was to assess the relationship between vitamin D levels, atopy markers, pulmonary function, and asthma severity.MethodsWe analyzed 25-hydroxyvitamin D levels in serum collected from 121 asthmatic adults from Costa Rica to investigate the association between vitamin D levels (categorized as sufficient, ≥30 ng/mL, or insufficient, <30 ng/mL), allergic rhinitis, total IgE and peripheral blood eosinophils (as markers of atopy), asthma severity, baseline forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC). Univariate and multivariate analyses were performed to assess these relationships.ResultsWhen the population was stratified by vitamin D status, 91% of asthmatic patients with vitamin D levels below 20 ng/mL (n=36) and 74% of patients with vitamin D levels between 20 and 30 ng/mL (n=73) had severe asthma versus 50% of those with vitamin D sufficiency (n=12; P=0.02). Vitamin D insufficiency was associated with a higher risk of severe asthma (odds ratio [OR], 5.04; 95% Confidence interval [CI], 1.23-20.72; P=0.02). High vitamin D levels were associated with a lower risk of hospitalization or emergency department visit during the last year (OR, 0.90; 95% CI, 0.84-0.98; P=0.04). Although there appeared to be a direct relationship between vitamin D levels and FEV1 (regression coefficient=0.48; r2=0.03), it did not reach statistical significance (P=0.07).ConclusionsOur findings suggest that vitamin D insufficiency is common among our cohort of asthmatic adults. Lower vitamin D levels are associated with asthma severity.

An update on vitamin D and human immunity

In the last 5 years, there has been a remarkable change in our understanding of the health benefits of vitamin D. The classical actions of vitamin D as a determinant of mineral metabolism and rachitic bone disease have been expanded to include a broader role in skeletal homoeostasis and prevalent bone disorders such as osteoporosis. However, it is the nonskeletal function of vitamin D that has attracted most attention. Although pluripotent responses to vitamin D have been recognized for many years, our new perspective on nonclassical vitamin D function stems from two more recent concepts. The first is that impaired, vitamin D status is common to many populations across the globe. This has prompted studies to explore the health impact of suboptimal circulating levels of vitamin D, with association studies linking vitamin D 'insufficiency' to several chronic health problems including autoimmune and cardiovascular disease, hypertension and common cancers. In support of a broader role for vitamin D in human health, studies in vitro and using animal models have highlighted immunomodulatory and anticancer effects of vitamin D that appear to depend on localized activation of vitamin D. The conclusion from these reports is that many nonclassical actions of vitamin D are independent of conventional vitamin D endocrinology and are therefore more sensitive to variations in vitamin D status. The current review summarizes these developments, with specific reference to the newly identified effects of vitamin D on the immune system, but also highlights the challenges in translating these observations to clinical practice.

Vitamin D, osteocalcin, and risk for adiposity as comorbidities in middle school children

Nonclassic actions of vitamin D include potential regulation of immune function and glucose homeostasis. The bone-metabolism loop has recently been expanded to include osteocalcin, which appears to play a more direct role in pancreatic beta cell function and energy metabolism. We hypothesized that both vitamin D and osteocalcin would correlate negatively with indices of adiposity-related comorbidity risk in periadolescents, varying by ethnic group. We analyzed anthropometric, metabolic, and inflammatory markers from a multiethnic population of 106 school children 11 to 14 years of age studied as part of the Reduce Obesity and Diabetes (ROAD) consortium. As expected, 25-hydroxyvitamin D (25-OH vitamin D) was inversely correlated with intact parathyroid hormone (iPTH); total osteocalcin (OCN) and uncarboxylated osteocalcin (uOCN) were directly correlated with each other. OCN and uOCN concentrations correlated inversely with age. Vitamin D deficiency was most prevalent among East Asians (EA) and African Americans (AA). The highest lipid risk scores and homeostatic model for assessment of insulin resistance (HOMA-IR) values were seen in the South Asian (SA) group. Overall, adiposity measures were inversely correlated with OCN and iPTH, whereas such relationships were not observed for vitamin D. Acute insulin response to glucose challenge correlated negatively with uOCN in all subjects; however, lipid risk score correlated negatively with uOCN only in whites. The relationships between markers of calcium metabolism and body composition, glucose homeostasis, lipids, and inflammation all showed racial and ethnic differences. No consistent relationship was found between vitamin D and adiposity or vitamin D and glucose metabolism; instead vitamin D levels varied by race and ethnicity in this school-based group. These findings are consistent with the hypothesis that markers of calcium and bone metabolism may reflect risk for adiposity-related comorbidities in children.

NUCLEAR RECEPTORS

NUCLEAR RECEPTORS

Hepatocellular carcinoma and vitamin D: A review

The non-classical actions of vitamin D, namely antiproliferation, pro-differentiation, pro-apoptosis, anti-inflammation, and immune regulation, have received great attention during the past decade. Increasing evidence from epidemiological studies showing the inverse association between vitamin D status and incidence of many forms of cancer as well as biochemical studies has suggested that vitamin D deficiency may play a role in the cause and progression of these types of cancer. Recently, vitamin D and its analogs have been deemed as potential regimen to treat a variety of cancers alone or in combination with other drugs. Although, the epidemiologic evidence regarding the association of vitamin D and hepatocellular carcinoma (HCC) is still inconclusive, biochemical evidence clearly indicates that HCC cells are responsive to the inhibitory effect of vitamin D and its analogs. In this review, we discuss the current status of HCC and its treatment, the source, metabolism, functions, and the mechanism of actions of vitamin D, and the biochemical studies of vitamin D analogs and their implications in the prevention and treatment of HCC.

Vitamin d and pancreatic cancer-an update.

The non-classical actions of vitamin D, namely anti-proliferation, pro-differentiation, immune function modulation, and anti-inflammation, have received great attention during the past decade, in particular, the potential of vitamin D analogs alone or in combination with other anticancer agents for the treatment of a variety of cancers. The association between vitamin D status and the higher incidence of many forms of cancer has suggested that vitamin D may play a role in the etiology of these types of cancer. Although it is still controversial whether this association exists for pancreatic cancer, biochemical evidence clearly indicates pancreatic cancer cells are responsive to the inhibitory effect of vitamin D and its analogs. In this review, we discuss briefly the origin and current therapy of pancreatic cancer, the history, source, metabolism and functions of vitamin D, the recent progress in the epidemiological studies of sunlight, and vitamin D status, and biochemical studies of vitamin D analogs in the prevention and treatment of pancreatic cancer.

Renoprotective effects of vitamin D analogs

Recent decades have witnessed the revelation of expanding roles of the vitamin D endocrine system beyond calcium and phosphorus metabolism. Along with these non-calcemic or non-classic actions of vitamin D are newly discovered therapeutic actions of vitamin D analogs in a number of pathological conditions, including kidney disease. The kidney is the major organ involved in the synthesis of the hormonal metabolite of vitamin D, and vitamin D deficiency is a common feature of chronic kidney disease even in its early stages. Experimental data suggest that vitamin D deficiency may in turn accelerate the progression of kidney disease. Low-calcemic vitamin D analogs have exhibited impressive therapeutic effects in various kidney disease models, with targets ranging from the NF-kappaB pathway to the renin-angiotensin system. These recent studies demonstrate that vitamin D analogs have potent renoprotective effects. The emerging experimental and clinical evidence has provided a solid foundation for the continuing exploration of vitamin D analogs in prevention and intervention in kidney disease.

Mechanisms involved in vitamin D mediated intestinal calcium absorption and in non-classical actions of vitamin D

Recent studies in our laboratory using calbindin-D 9k null mutant mice as well as mice lacking the 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3) inducible epithelial calcium channel TRPV6 provide evidence for calbindin-D 9k and TRPV6 independent regulation of active intestinal calcium absorption. These findings suggest that in the knock out (KO) mice there is compensation by another calcium channel or protein and that other novel factors are involved in 1,25(OH) 2D 3 mediated active intestinal calcium absorption. In addition, 1,25(OH) 2D 3 mediated paracellular transport of calcium may have contributed to the normalization of serum calcium in the null mutant mice. 1,25(OH) 2D 3 downregulates cadherin-17 and upregulates claudin-2 and claudin-12 in the intestine, suggesting that 1,25(OH) 2D 3, by regulating these epithelial cell junction proteins, can route calcium through the paracellular path. With regard to non-classical actions, 1,25(OH) 2D 3 has been reported to inhibit the proliferation of a number of malignant cells and to regulate adaptive as well as innate immunity. This article will review new developments related to the function and regulation of vitamin D target proteins in classical and non-classical vitamin D target tissues that have provided novel insight into mechanisms of vitamin D action.

Nonclassic actions of vitamin D and its clinical significance

长期以来对血清25(OH)D理想水平一直缺乏共识,判定维生素D缺乏的标准也不一致,但多数专家赞同将25(OH)D水平低于50 nmol/L(20 ng/ml)定为维生素D缺乏,而将52-72 nmol/,L(21-29ng/ml)定为维生素D相对不足,＞75 nmol/L(30ng/ml)为维生素D充足.按照这个标准,维生素D缺乏是全球性的.估计有10亿人患维生素D缺乏或相对不足[1]。

Vitamin D deficiency during pregnancy may impair maternal and fetal outcomes

Over the past decade, new evidence has shown that vitamin D deficiency may contribute to the risk of developing a wide range of common chronic diseases that are different from the classic action on calcium and bone homeostasis. Acting through the vitamin D receptor, vitamin D can produce a wide array of favorable biological effects via genomic, non-genomic or intracrine mechanisms and, therefore, contributes to the improvement of human health in humans. We hypothesize that some of these effects may be even more critical during pregnancy. The focus of this paper is to review the data on the classic and non-classic actions of vitamin D with regards to pregnancy. It appears that vitamin D insufficiency during pregnancy is potentially associated with increased risk of preeclampsia, insulin resistance and gestational diabetes mellitus. Furthermore, experimental data also anticipate that vitamin D sufficiency is critical for fetal development, and especially for fetal brain development and immunological functions. Vitamin D deficiency during pregnancy may, therefore, not only impair maternal skeletal preservation and fetal skeletal formation but also be vital to the fetal "imprinting" that may affect chronic disease susceptibility soon after birth as well as later in life.

Vitamin D, a neuro-immunomodulator: Implications for neurodegenerative and autoimmune diseases

It has been known for more than 20 years that vitamin D exerts marked effects on immune and neural cells. These non-classical actions of vitamin D have recently gained a renewed attention since it has been shown that diminished levels of vitamin D induce immune-mediated symptoms in animal models of autoimmune diseases and is a risk factor for various brain diseases. For example, it has been demonstrated that vitamin D (i) modulates the production of several neurotrophins, (ii) up-regulates Interleukin-4 and (iii) inhibits the differentiation and survival of dendritic cells, resulting in impaired allo-reactive T cell activation. Not surprisingly, vitamin D has been found to be a strong candidate risk-modifying factor for Multiple Sclerosis (MS), the most prevalent neurological and inflammatory disease in the young adult population. Vitamin D is a seco-steroid hormone, produced photochemically in the animal epidermis. The action of ultraviolet light (UVB) on 7-dehydrocholesterol results in the production of pre-vitamin D which, after thermo-conversion and two separate hydroxylations, gives rise to the active 1,25-dihydroxyvitamin D. Vitamin D acts through two types of receptors: (i) the vitamin D receptor (VDR), a member of the steroid/thyroid hormone superfamily of transcription factors, and (ii) the MARRS (membrane associated, rapid response steroid binding) receptor, also known as Erp57/Grp58. In this article, we review some of the mechanisms that may underlie the role of vitamin D in various brain diseases. We then assess how vitamin D imbalance may lay the foundation for a range of adult disorders, including brain pathologies (Parkinson's disease, epilepsy, depression) and immune-mediated disorders (rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus or inflammatory bowel diseases). Multidisciplinary scientific collaborations are now required to fully appreciate the complex role of vitamin D in mammal metabolism.

Nonclassic Actions of Vitamin D

Vitamin D receptors are found in most tissues, not just those participating in the classic actions of vitamin D such as bone, gut, and kidney. These nonclassic tissues are therefore potential targets for the active metabolite of vitamin D, 1,25(OH)(2)D. Furthermore, many of these tissues also contain the enzyme CYP27B1 capable of producing 1,25(OH)(2)D from the circulating form of vitamin D. This review was intended to highlight the actions of 1,25(OH)(2)D in several of these tissues but starts with a review of vitamin D production, metabolism, and molecular mechanism. Medline was searched for articles describing actions of 1,25(OH)(2)D on parathyroid hormone and insulin secretion, immune responses, keratinocytes, and cancer. Vitamin D production in the skin provides an efficient source of vitamin D. Subsequent metabolism to 1,25(OH)(2)D within nonrenal tissues differs from that in the kidney. Although vitamin D receptor mediates the actions of 1,25(OH)(2)D, regulation of transcriptional activity is cell specific. 1,25(OH)(2)D inhibits PTH secretion but promotes insulin secretion, inhibits adaptive immunity but promotes innate immunity, and inhibits cell proliferation but stimulates their differentiation. The nonclassic actions of vitamin D are cell specific and provide a number of potential new clinical applications for 1,25(OH)(2)D(3) and its analogs. However, the use of vitamin D metabolites and analogs for these applications remains limited by the classic actions of vitamin D leading to hypercalcemia and hypercalcuria.