Synthesis and Metabolism of Vitamin D
Vitamin D is neither a vitamin nor a hormone, and is created when adequate exposure to sunlight is available to promote the synthesis of vitamin D in the skin . When human skin is exposed to sunlight, it is the solar ultraviolet B photons between 290 and 315 nm that are responsible for causing the photolysis of 7-dehydrocholesterol (provitamin D3; the immediate precursor in the cholesterol biosynthetic pathway) to previtamin D3 [2, 3].
The metabolism of vitamin D in the skin is a multi-step process that starts from 7-dehydrocholesterol (7-DHC) [4-6]. 7-DHC is present mainly in the stratum spinosum and stratum basale of the epidermis. It is s a strong UV absorber with 3 λmax around 270- 280 nm and 295 nm. It is partly photolyzed by UV radiation to create previtamin D3. Previtamin D3 is rapidly isomerized into inactive vitamin D3, which then undergoes hydroxylation in epidermal keratinocytes to produce active Vitamin D3 1α,25(OH)2-cholecalciferol (1α,25(OH)2. After binding to carrier proteins, particularly vitamin D-binding protein (DBP), vitamin D3 is transported to the liver [1, 2, 7], where it becomes finally hydroxylated to hormonally active calcitriol (1,25-dihydroxyvitamin D3). 1,25(OH)2D3 exerts its actions via the vitamin D receptor (VDR), a member of the hormone nuclear receptor superfamily, and a second, yet to be identified, membrane receptor. While the importance of vitamin D3 for bone health has been known for decades, only in more recent years an immunomodulatory role for 1,25(OH)2D3 has been identified. 1,25(OH)2D3 affects the differentiation and function of dendritic Cells (DCs), T cellsand B cells. In vitro1,25(OH)2D3 can alter the function of DCs by inhibiting their differentiation and maturation, which may lead to the induction of regulatory T cells or to the poor activation of antigen-specific T cells (reviewed in ).
Calcitriol is transported by DBP to vitamin D receptor (VDR)-positive target tissues  and is mediating its effects by binding to the VDR . Taken together, sunlight supplies most requirements for the synthesis of vitamin D. Calcitriol acts in the kidney, but is also transported by DBP to VDR-positive target tissues . Calcitriol is acting as an inductor of proteins and is modulating the immune system. Calcitriol is increasing the level of calcium (Ca2+) in the blood by the uptake of calcium from the gut into the blood, and possibly increasing the release of calcium into the blood from bone. The hydroxylation reaction in the formation of active calcitriol is an important control point in Ca2+ homeostasis .
The active form of D-vitamins is calcitriol, also known as 1α,25(OH)2-cholecalciferol (1α,25(OH)2Vitamin D3) or ( 1,25(OH)2D3. Vitamin D is a secosteroid. Secosteroids are naturally occurring chemical substances based on steroids. The steroids (including vitamin D) spontaneously pass through the membranes of their target cells to the cytosol, where they bind to their cognate receptors. The steroid–receptor complexes then migrate to the cell nucleus, where they function as transcription factors to induce, or in some cases repress, the transcription of specific genes. .
Vitamin D and its analoga exhibit modulating properties on inflammatory responses of the immune system. From the therapeutical point of view the effects are still uncovered. An example is the down regulation of the release of TNF-α and interleukin 1 in psoriatic lesions .
Several vitamin D analogs (e.g. calcitriol, calcipotriol, tacalcitol and maxacalcitol) have been synthesized for topical psoriasis therapy. These agents show anti-proliferative and prodifferentiating effects on human keratinocytes in vitro and in vivo .
Numerous in vitro and in vivo studies have demonstrated dose-dependent effects of vitamin D Analogs on cell proliferation and differentiation. At low concentrations, calcitriol promotes the proliferation of keratinocytes in vitro; at higher pharmacological doses (≥10-8 M ) keratinocyte proliferation is inhibited . Although the mechanisms that underlie the anti-proliferative and differentiation-inducing effects of vitamin D analogs on keratinocytes are not completely understood, it is well known that these effects are at least in part genomic and mediated via the vitamin D receptor (VDR) .
Remarkably calcitriol exhibits an antioxidative effect in keratinocytes. Since a couple of years the knowledge arises that different analogs of vitamin D modulate apoptosis and may even inhibit the growth of malign cells . These trend setting experiments from Evans et al. were performed with cell lines. However, analyzing an extensive literature search of many case reports, we established the positive effect of the release of vitamin D in sarcoidosis. We realized, that vitamin D is killing malign cells and is leading in many cases to the remission of the tumor .
Immunomodulatory effects in the skin
The active form of vitamin D3, 1,25(OH)2D3, is known, besides its classical effects on calcium and bone, for its pronounced immunomodulatory effects that are exerted both on the antigen-presenting cell level as well as directly on the T lymphocyte level. In animal models, these immune effects of 1,25(OH)2D3are reflected by a strong potency to prevent onset and even recurrence of autoimmune diseases . During recent years, new and important immunomodulatory effects of vitamin D analogs have been characterized . NF-κB has long been considered a prototypical proinflammatory signaling molecule largely based on the activation of NFκB by proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor α (TNFα) as wll as its role in the expression of other proinflammatory genes including cytokines, chemokines, and adhesion molecules . The nuclear factor kappa B ((NFκB) is a very important factor activated by cellular stress. It acts as a transcription factor. NFκB plays a central role as an important immune response regulator at inflammatory sites . TNFα is a major mediator of host response to pathogens, in that, it initiates a powerful proinflammatory cascade, which promotes massive recruitment of leukocytes at the infected site.
These inflammatory responses are mediated by changes of the expression of many genes. NFκB is a major regulator of gene transcription involved in immune, inflammatory and stress responses. It consists of five proteins which tend to dimerize and are thus kept in the cytoplasm through interaction with IkB inhibitory proteins. . The most dominant protein in the NFκB family is the p65 protein and the best-characterized interaction is that of the transcriptionally active p65 with p50 .
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. It is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LD, and bacterial or viral antigens
An introduction into the human part of the NFkB family of proteins is described by Gilmore . In short: the NF-B family of proteins is composed of two subfamilies: the ‘NF-B’ proteins and the ‘Rel’ proteins. All of these proteins share a highly conserved DNA-binding/dimerization domain called the Rel homology domain (RHD). The NFB proteins consist of five subunits including the following members:
1. NF-κB1 (p50)
2. NF-κB2 (p52)
3. RelA (p65)
The Rel subfamily includes c-Rel, RelB and RelA. The members of the NF-kB subfamily become activators of transcription when they form dimers with members of the Rel subfamily. The NF-kB transcription factor dimers bind to 9–10 base pair DNA sites (kB sites) which are localized in the promotor region of genes.
the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, p105, and p100, which undergo processing to generate the mature NF-κB subunits, p50 and p52, respectively. The NF-kB proteins become shorter, active DNA-binding proteins (p105 to p50 and p100 to p52) . As such, members of the NF-kB subfamily are generally not activators of transcription, except when they form dimers with members of the Rel subfamily. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens [21-25] . The non-dimerized and inactive NFkB proteins are sequestered in the cytoplasm by inhibitor proteins called IκBs. These proteins mask the nuclear localisation signal of the non activated NFkB molecules thereby inhibiting the transport into the nucleus and keeping the non activated molecules in the cytoplasm . NF-κB is maintained in an inactive form by sequestration in the cytoplasm through interaction with inhibitory proteins, the IκBs. Proteolytic degradation of IκB immediately precedes and is required for NF-κB nuclear translocation. NFκBs are present in virtually every cell type, but is retained in the cytoplasm in an inactive form bound to specific inhibitors, the IκBs.
NF-κB is maintained in an inactive form by sequestration in the cytoplasm through interaction with inhibitory proteins, the IjBs. Proteolytic degradation of IjB immediately precedes and is required for NF-κB nuclear translocation. of NFκBs .
NFκB has long been considered as the prototypical proinflammatory molecule. It is involved in the expression of inflammatory proteins, including, cytokines, and chemokines and adhesion molecules. This idea was supported by data demonstrating the activation of NFκB by proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor α (TNFα  and NFκB is involved in the induction of genes of both, the inate and the adaptive immune response . IL-1 and TNFα are archetypic proinflammatory cytokines that are rapidly released on tissue injury or infection. The defense against invading microbes in an injured area is supported an additionally induced by Toll-like microbial pattern recognition receptors (TLRs) as it is described on our internet pages dealing with wound healing.
Toll-like microbial pattern recognition receptors in wound healing
Endogenous ligands may trigger TLRs during tissue injury and certain disease states, may act to promote inflammation in the absence of infection . In addition, the expression of cathelicidin LL-37 and β-defensin 2 in the skin is induced by low dose UV radiation in parallel with the up-regulation of the cutaneous vitamin D3 system .
Vitamin D in cosmetics
Sunscreens absorb ultraviolet B (UVB) and it is a major concern that sunscreen use may lead to vitamin D deficiency . Using sunscreens an increase in vitamin D was reduced as sunscreen thickness increased, and that an inverse exponential model could fairly well describe this relationship between sunscreen thickness and increase in vitamin D [30, 31]. One of the major concerns is that sunscreen use may decrease vitamin D formation in the skin. This is alarming as vitamin D is important for bone structure, and epidemiological studies have shown that vitamin D deficiency is associated with a wide range of other diseases including Cancer and autoimmune diseases as multiple sclerosis, type1 diabetes and rheumatoid arthritis.[32-36]. In “artificial” study situations sunscreen use can adversely affect vitamin D production in that sunscreens can suppress vitamin D production . As most people do not apply sunscreens as thickly as advised the exponential effect of sunscreen thickness on vitamin D increase after UVB exposure contributes to explaining this paradox [31, 37]. The results of studies analyzing sunscreen use and vitamin D production are contradictive which results not only from different study conditions particularly between clinical studies and discrepancies between study design and real-life situation, summarized in Faurschou et al. . The authors showed in this study that the vitamin D serum level increases in an exponential manner with decreasing thickness of sunscreen layer in response to ultraviolet B exposure. They demonstrate that sunscreen application thickness is important and explain the discrepancy between studies in real-life situations and under controlled conditions .
Vitamin D in cancer
Vtamin D is a necessary substance for life whose synthesis in the skin is induced by ultraviolet radiation. Sunlight is the main source of UV light for vitamin D photosynthesis in man. But it is also the main risk factor for both melanocytic and non-melanocytic skin cancer.
Currently, there are active research efforts, as well as scientific debate, about a number of mechanisms, including ant proliferative effects and potential influences on cell differentiation and angiogenesis . Observational epidemiological studies are providing more plentiful evidence that high levels of vitamin D might protect against certain types of cancer, such as cancer of the bowel  and breast .
The summary of a critical review of the main conclusions from the report of the IARC working group about cancers and observational studies with significant relevanc are for colorectal cancer and breast cancer similar. The epidemiological observational evidence for these two cancer support a role of vitamin D in reducing the risk of colorectal cancer and a similar result for breast cancer protection, However results from observational studies and randomized controlled trials RCTs) suggest that vitamin D supplements may lower all-cause mortality .
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-VD), inhibits proliferation and induces differentiation in human prostate cancer cell lines. Prostate cancer cells respond to vitamin D(3) with increases in differentiation and apoptosis, and decreases in proliferation, invasiveness and metastasis . 25-hydroxyvitamin D 25-VD) is the main indicator of vitamin D status .The data of this study show an inverse association between serum concentration of 25-VD, and prostate cancer risk .
Levels of Vitamin D in cardiometabolic dismorders (CVD)
Hypertension, dyslipidema, central obesity and glycogenic dysregulation are known risk factors for CVD . Vitamin D deficiency is also highly prevalent in different populations across the world. Studies suggest that approximately 30–50% of the adult population is at risk of vitamin D deficiency [45, 46]. Vitamin D is known to play an important role in bone and mineral homeostasis and has also been linked with multiple other pathophysiological mechanisms. There is also growing evidence to support the link between abnormal levels of vitamin D and CVD and diabetes mellitus (DM) [45, 47, 48]. The authors of this study showed a connection between vitamin D levels on potential risk of developing cardio metabolic disorders (CVD, DMand MetS). They claim the suggestion, that high levels of vitamin D, among adult populations, are associated with a substantial decrease in cardiovascular disease, type 2 diabetes and metabolic syndrome .
There is evidence, that there are beneficial effects of vitamin D on the autoimmune diseases: multiple sclerosis, type 1 diabetes and rheumatoid arthritis. These diseases are T helper type 1-mediated and benefit from the vitamin D effects. Thereby UVR exposure may be one factor that can attenuate the autoimmune activity. UVR-derived vitamin D synthesis provides some support for a beneficial role of UVR . These three autoimmune diseases are characterized by a breakdown in immunological self-tolerance that may be initiated by an inducing agent, such as an infectious microorganism .
Usually the immune repertoire is consisting from immune cells stemming from central lymphoid organs, thymus, and bone marrow the generation of the cellular repertoire is accompanied by deletion of self reactive lymphocytes by apoptosis. The “leakiness” of this process requires back up by peripheral tolerance. This process might fail because of the interaction of a wrong environment with the wrong genes. There exist different possibilities to circumvent the normally thigh control to prevent the acivytion of self reactive lymphocytes. These include ignorance, anergy, homoeostatic control, and regulation.
Environmental agents can cause autoimmunity, but only the luckless few with the wrong genes will actually succumb. Infection is strongly implicated because it can readily disrupt peripheral tolerance in ways that include exposure of self to the immune system through breakdown of vascular or cellular barriers .
Antimicrobial defense in psoriasis
The specific cause for psoriasis is unknown but a large body of evidence has identified a dysregulated interplay between keratinocytes and inflammatory cell infiltrates underlying cutaneous inflammation . human keratinocytes stimulated with supernatants from T cells isolated from lesional psoriatic skin increasedthe expression of cathelicidin when stimulated in the presence of Calcitriol ( 1,25-dihydroxyvitamin D 3) / 1,25(OH)2D3),) . Recently the participation of innate anti- microbial peptides like cathelicidin peptide LL-37 are enabling the response to self-DNA by plasmacytoid dendritic cells (pDC) and therefore may participate in the activation of psoriasis. Thus, a mechanism has been hypothesized by which pDC sense and respond to self-DNA coupled with cathelicidin peptide LL-37, which drives autoimmunity in psoriasis . These results indicate a fundamental role of cathelicidin in activating cutaneous inflammation in psoriasis . In psoriasis, cathelicidin expression in keratinocytes is increased compared with healthy skin . This observation may explain in part the relative resistance to cutaneous infections seen in patients with psoriasis.
The interplay between keratinocytes and infiltrating immue cells in the skin of psoriasis patient is deregulated . Cytokines and other soluble factors such as antimicrobial peptides (AMPs) secreted by resident or infiltrating cells are essential elements in this process of cell-cell communication. In lesional skin in psoriasis antimicrobial peptides (AMPs) are strongly expressed and play an important role as proinflammatoryalarmins .
AMPs are a first barrier of defence against microbial pathogens . AMPs has been identified and due to their multiple functions as activators of adaptive immune responses and inflammation the term “alarmins” has been introduced .
Vitamin D in atopic dermatitis
Vitamin D influences allergen-induced pathways in the innate and adaptive immune system  mediated by NF B . The vitamin D receptor (VDR) finds expression in several inflammatory cells, including T cells, B cells, neutrophils, macrophages, and dendritic cells . Vitamin D enhances expression of antimicrobial peptides (AMPs) (including cathelicidin and β-defensins), enhances skin barrier function, induces autophagy in macrophages, and induces natural killer cells via increased cathelicidin [61-63]. Vitamin D is also involved in decreasing excessive inflammation by suppressing Toll-like receptor production by monocytes, enhancing mast cell production of interleukin-10 (IL-10, an anti-inflammatory cytokine), Because atopic dermatitis (AD), chronic urticaria, and allergic contact dermatitis (ACD) all involve immune dysregulation, the role of vitamin D has been explored in these three common allergic skin disorders. The pathogenesis of AD is complex and multifactorial, involving abnormalities in cells of the immune system and the skin barrier. Patients with AD are more likely to acquire staphylococcal or viral infections of the skin due to three major factors: a compromised physical barrier of the epidermis, defects in pattern recognition receptors, and diminished production of AMPs during inflammation .
The difference difference between Psoriasis and AD in this topic is described above and in the psoriasis chapter. https://www.molcare-consulting.com/skin-research/psoriasis.html
It has been suggested that vitamin D supplementation (via UV light exposure or oral supplements) is beneficial for AD. Interestingly, Norwegian children with AD, not strongly exposed to UV light due to the local living conditions, were exposed for 4 weeks to the sunny subtropical climate in Gran Canary for 4 weeks, and showed significantly improved SCORAD indices  For the scoring of the severity of AD the so called “SCORing Atopic Dermatitis” (SCORAD) has been utilized. Peroni et al. found that serum levels of 1,25-VD were significantly higher in children with mild AD compared to those with moderate or severe disease, based on SCORAD . The serum levels of 1,25-VD were associated with a higher SCORAD index as well as an increased risk of food allergen sensitization .
In contrast to the observed resistance to bacterial infections in Psoriasis patients, the skin of patients with AD frequently becomes colonized with S. aureus. Because AD can be worsened by an overlying bacterial infection, an observational, cross-sectional study investigated the relationship between levels of vitamin D and S. aureus virulence factors .
Taken together, the results of many studies suggest, that vitamin D is protective against AD .
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