**2. Role of vitamin D in immune regulation and inflammatory responses**

The first data concerning the potential role for VD and its active metabolite 1,25(OH)2D in modulating the immune response were obtained as a result of the treatment of tuberculosis and leprosy caused by mycobacteria [1]. However, the mechanisms underlying these observations have been clarified more recently with several important discoveries: (1) the upregulation of CYP27B1 and VDR expression in activated human inflammatory cells, thus providing their ability both to produce 1,25(OH)2D in the site of inflammation and to respond to this hormonally active metabolite; and (2) the participation of 1,25(OH)2D in modulating the multiple pathways of the innate and adaptive immune system. The influence of 1,25(OH)2D on the different cell types of these immune system segments is outlined in **Figure 1**.

Innate immune response involves the activation of Toll-like receptors in monocytes/macrophages as well as in a number of cells such as placenta trophoblasts, keratinocytes, and epithelial, intestinal, lung, and corneal cells, representing first-barrier defenses. VD affects innate immunity through its stimulatory action on the synthesis of defensin β2 and cathelicidin antimicrobial peptide (CAMP) upon Toll-like receptors' activation. These low molecular weight host defense

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**Figure 1.**

antimicrobial peptides demonstrate a broad spectrum of activity against bacteria, viruses, and fungi in the immune cells and are also synthesized in a variety of other cell types [1]. CAMP is known to be a direct transcriptional target of VD, which is induced by binding of 1,25(OH)2D-VDR/retinoid X receptor (RXR) complex to the VD response elements (VDRE) in the gene promoter [2]. VD can also modulate innate immune system by increasing chemotaxis, autophagy, and phagolysosomal fusion of phagocytic cells. Notably, VD's action on macrophages was established to be modulated by interleukins. In particular, VD increases the antimicrobial activity of macrophages formed after the IL-15 stimulus, while phagocytic macrophages do

*Vitamin D in immune modulation. 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25OHD, 25-hydroxyvitamin D; IFN-γ, interferon-γ; ILs, interleukins; TGF-β, transforming growth factor β; Th1, type 1 T helper; Th2, type 2* 

*T helper; Th17, type 17 T helper; TNF-α, tumor necrosis factor-α; Treg, regulatory T cells.*

*Vitamin D Deficiency and Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.89543* *Vitamin D Deficiency*

form–1,25(OH)2D. 1,25(OH)2D through VDR controls the expression of both those genes that participate in mineral homeostasis and bone remodeling, and genes (about 500) that participate in various cellular pathways that affect physiological and cellular mechanisms, such as immunomodulation, hormone secretion, inhibi-

Recent epidemiological studies have indicated the association between VD deficiency and both type 1 (T1D) and type 2 (T2D) diabetes mellitus. Moreover, impaired glucose tolerance and diabetes have been shown to ameliorate in

VD-deficient individuals after VD supplementation. Vitamin D deficiency, which may be a key factor for diabetes development, is prevalent around the globe, with an estimated one billion people being vitamin D deficient. The role of VD in diabetes became clearer after the discovery of VDR in the pancreas, adipose tissue, skeletal muscle cells, and immune cells, which indicates a regulatory effect of VD on glucose homeostasis. Vitamin D can directly enhance insulin synthesis and its release from pancreatic β-cells as well as increase the expression of the insulin receptor in peripheral tissues. It can also indirectly exert an antidiabetic effect by acting on cells of the immune system that secrete pro-inflammatory cytokines as mediators affecting weight gain, systemic inflammation (contributes to insulin resistance), and autoimmune-mediated destruction of pancreatic β-cells. These findings suggested that VD deficiency probably has a causal relationship with diabetes mellitus. Some studies have also reported that VD deficiency was not the cause, but the result of diabetes. Regardless of whether this deficiency is one of the causes of diabetes or its consequence, it is obvious that low levels of VD are closely associated with poor regulation of diabetes and its complications; however, the extent of this relationship

The aim of the present chapter is to summarize the latest evidence linking VD insufficiency/deficiency with the development of T1D and T2D and their complications. We also analyzed different intervention studies with VD supplements to determine their influence on glucose metabolism and delineated the underlying mechanisms. Previous reviews on the role of VD in diabetes mellitus have been published in recent years. Here, priority was given to the most recent and convinc-

**2. Role of vitamin D in immune regulation and inflammatory responses**

The first data concerning the potential role for VD and its active metabolite 1,25(OH)2D in modulating the immune response were obtained as a result of the treatment of tuberculosis and leprosy caused by mycobacteria [1]. However, the mechanisms underlying these observations have been clarified more recently with several important discoveries: (1) the upregulation of CYP27B1 and VDR expression in activated human inflammatory cells, thus providing their ability both to produce 1,25(OH)2D in the site of inflammation and to respond to this hormonally active metabolite; and (2) the participation of 1,25(OH)2D in modulating the multiple pathways of the innate and adaptive immune system. The influence of 1,25(OH)2D on the different cell types of these immune system segments is outlined

Innate immune response involves the activation of Toll-like receptors in monocytes/macrophages as well as in a number of cells such as placenta trophoblasts, keratinocytes, and epithelial, intestinal, lung, and corneal cells, representing first-barrier defenses. VD affects innate immunity through its stimulatory action on the synthesis of defensin β2 and cathelicidin antimicrobial peptide (CAMP) upon Toll-like receptors' activation. These low molecular weight host defense

tion of cell proliferation, and induction of cell differentiation.

and its clinical relevance are not well established.

ing available evidence.

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in **Figure 1**.

#### **Figure 1.**

*Vitamin D in immune modulation. 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25OHD, 25-hydroxyvitamin D; IFN-γ, interferon-γ; ILs, interleukins; TGF-β, transforming growth factor β; Th1, type 1 T helper; Th2, type 2 T helper; Th17, type 17 T helper; TNF-α, tumor necrosis factor-α; Treg, regulatory T cells.*

antimicrobial peptides demonstrate a broad spectrum of activity against bacteria, viruses, and fungi in the immune cells and are also synthesized in a variety of other cell types [1]. CAMP is known to be a direct transcriptional target of VD, which is induced by binding of 1,25(OH)2D-VDR/retinoid X receptor (RXR) complex to the VD response elements (VDRE) in the gene promoter [2]. VD can also modulate innate immune system by increasing chemotaxis, autophagy, and phagolysosomal fusion of phagocytic cells. Notably, VD's action on macrophages was established to be modulated by interleukins. In particular, VD increases the antimicrobial activity of macrophages formed after the IL-15 stimulus, while phagocytic macrophages do

not respond to vitamin D after the IL-10 stimulus, regardless of their high phagocytic activity [1, 3].

Vitamin D shows an inhibitory action on the adaptive immune system, the responses of which include the ability of T and B lymphocytes to produce cytokines and immunoglobulins, respectively, to specifically combat antigens presented to them by macrophages and dendritic cells (DCs). Experimental studies have yielded encouraging results on the immunomodulatory effect of calcitriol on T helper (Th) cells. In particular, 1,25(OH)2D was shown to suppress the immune responses mediated by Th1 cells capable of producing such pro-inflammatory cytokines as IL-2, IL-6, interferon γ (IFN-γ), and tumor necrosis factor-α (TNF-α) [4]. The lack of IFN-γ prevents further antigen presentation to T lymphocytes and their recruitment, while lower IL-2 production impedes T lymphocyte proliferation and differentiation. It has been recently demonstrated that calcitriol also increases formation and activity of CD4+/CD25+ regulatory T cells (Treg) as seen by elevated FoxP3 and IL-10 expression [5]. Increased levels of IL-10 as well as other cytokines with anti-inflammatory properties, induced by calcitriol, block Th1 differentiation, thus shifting the balance from Th1 to Th2 cell phenotype [6]. Many of the effects of VD on Th1 cells, which were previously considered to be implicated in the pathogenesis of several autoimmune diseases, can now be attributable, at least in part, to the inhibitory action of 1,25(OH)2D on the formation and activity of Th17 cells, producing IL-17 [5]. The overall impact of VD on Th cells is related to the suppression of antigen-presenting cells (APCs) of the innate immune system, including the most potent dendritic cells. This modulatory effect of 1,25(OH)2D induces a "tolerogenic state" associated with the differentiation of Treg cells, autoreactive T cell apoptosis, reduced production of inflammatory cytokines, and increased levels of the anti-inflammatory cytokines.

Chromatin immunoprecipitation assay revealed VDR binding to a VDRE in the proximal area of IL-10 promoter in antibody-producing cells of the immune system, or B-cells [7]. 1,25(OH)2D blocked the proliferation of activated B-cells and stimulated their apoptosis. It also inhibited maturation of activated B-cells into plasma cells and memory cells that is consistent with the inhibitory action of VD on the secretion of IgM and IgG [8]. Several observational trials showed an inverse relationship between serum IgE and 25OHD levels, while others indicated a positive correlation [9].

Due to the ability of VD to suppress the adaptive immune system, the role of VD deficiency and supplementation in inflammatory and autoimmune diseases acquires more comprehensive support. In a number of animal models, including autoimmune diabetes, inflammatory arthritis, experimental allergic encephalitis, and different mouse models of enterocolitis, calcitriol prevented the initiation and reduced the disease progression. However, despite strong experimental evidence, human studies are less convincing to prove a role for VD in the modulation of adaptive immune system of individuals affected by autoimmune diseases. In this respect, some trials have confirmed beneficial effect of VD on different inflammatory disease progression, inflammatory markers, and T cell subsets, whereas others have not shown any promising result [10, 11].
