Vitamin D: Classic and Novel Actions

Abstract

Background: Classically, vitamin D has been implicated in
bone health by promoting calcium absorption in the gut and
maintenance of serum calcium and phosphate concentrations,
as well as by its action on bone growth and reorganization
through the action of osteoblasts and osteoclasts cells.
However, in the last 2 decades, novel actions of vitamin D
have been discovered. The present report summarizes both
classic and novel actions of vitamin D. Summary: 1,25(OH) 2
vitamin D, the active metabolite of vitamin D, also known as
calcitriol, regulates not only calcium and phosphate homeostasis
but also cell proliferation and differentiation, and has
a key a role to play in the responses of the immune and nervous
systems. Current effects of vitamin D include xenobiotic
detoxification, oxidative stress reduction, neuroprotective
functions, antimicrobial defense, immunoregulation,
anti-inflammatory/anticancer actions, and cardiovascular
benefits. The mechanism of action of calcitriol is mediated
by the vitamin D receptor, a subfamily of nuclear receptors
that act as transcription factors into the target cells after
forming a heterodimer with the retinoid X receptor. This kind
of receptors has been found in virtually all cell types, which
may explain its multiple actions on different tissues. Key
Messages: In addition to classic actions related to mineral
homeostasis, vitamin D has novel actions in cell proliferation
and differentiation, regulation of the innate and adaptative
immune systems, preventive effects on cardiovascular and
neurodegenerative diseases, and even antiaging effects.

Full text

Review Article
Ann Nutr Metab 2018;72:87–95
Vitamin D: Classic and Novel Actions
ÁngelGila–d JulioPlaza-Diaza–c MaríaDoloresMesaa–c,e
aDepartment of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada, Spain;
bInstitute of Nutrition and Food Technology “José Mataix,” Biomedical Research Center, University of Granada,
Granada, Spain; cInstituto de Investigación Biosanitaria ibs GRANADA, Complejo Hospitalario Universitario de
Granada, Granada, Spain; dCIBEROBN (CIBER Physiopathology of Obesity and Nutrition CB12/03/30028), Instituto de
Salud Carlos III, Madrid, Spain; eThematic Networks of Cooperative Research-RETIC-, Carlos III Health Institute-ISCIII,
Maternal and Child Health Network (SAMID), RD16/0022/0003, Madrid, Spain
Received: December 28, 2017
Accepted: December 29, 2017
Published online: January 18, 2018
Prof. Angel Gil
Institute of Nutrition and Food Technology “José Mataix”
Biomedical Research Center, University of Granada
Avda. del Conocimiento s/n, ES–18016 Armilla, Granada (Spain)
E-Mail agil @ ugr.es
© 2018 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/anm
DOI: 10.1159/000486536
Keywords
Vitamin D · Calcitriol · Calcium · Novel actions
Abstract
Background: Classically, vitamin D has been implicated in
bone health by promoting calcium absorption in the gut and
maintenance of serum calcium and phosphate concentra-
tions, as well as by its action on bone growth and reorganiza-
tion through the action of osteoblasts and osteoclasts cells.
However, in the last 2 decades, novel actions of vitamin D
have been discovered. The present report summarizes both
classic and novel actions of vitamin D. Summary: 1,25(OH)2
vitamin D, the active metabolite of vitamin D, also known as
calcitriol, regulates not only calcium and phosphate homeo-
stasis but also cell proliferation and differentiation, and has
a key a role to play in the responses of the immune and ner-
vous systems. Current effects of vitamin D include xenobi-
otic detoxification, oxidative stress reduction, neuroprotec-
tive functions, antimicrobial defense, immunoregulation,
anti-inflammatory/anticancer actions, and cardiovascular
benefits. The mechanism of action of calcitriol is mediated
by the vitamin D receptor, a subfamily of nuclear receptors
that act as transcription factors into the target cells after
forming a heterodimer with the retinoid X receptor. This kind
of receptors has been found in virtually all cell types, which
may explain its multiple actions on different tissues. Key
Messages: In addition to classic actions related to mineral
homeostasis, vitamin D has novel actions in cell proliferation
and differentiation, regulation of the innate and adaptative
immune systems, preventive effects on cardiovascular and
neurodegenerative diseases, and even antiaging effects.
© 2018 S. Karger AG, Basel
Introduction
Vitamin D was first characterized like a vitamin in the
20th century and now it is recognized as a prohormone.
Two major forms of vitamin D are vitamin D2 (ergocal-
ciferol) and vitamin D3 (cholecalciferol). Vitamin D3 is
synthesized in the skin of humans and is consumed in the
diet via the intake of animal-based foods, mainly fish oils,
Presented at the IUNS Conference, Buenos Aires 2017.

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whereas vitamin D2 is derived from plant sources, is not
largely human-made, and added to foods [1]. Vitamins
D2 and D3 forms differ only in their side chain structure
(Fig.1). The differences do not affect metabolism (i.e.,
activation), and both forms have the prohormone func-
tion.
Vitamin D Absorption and Photobiogenesis
Vitamin D obtained from sun exposure, food, and
supplements is biologically inactive (either the vitamin
D2 or D3) and must undergo activation through 2 con-
secutive enzymatic hydroxylation reactions occurring in
the liver and kidney (Fig.1).
Dietary vitamin D (either vitamin D2 or D3) is usually
absorbed at the small intestine with other dietary fats [2].
The presence of fats in the lumen triggers bile acids re-
lease, which initiate emulsification and support the for-
mation of lipid-containing micelles, which diffuse into
enterocytes [3]. Once absorbed, exogenous vitamin D is
packaged into chylomicrons, and thus is transported to
the liver. A fraction of the vitamin D contained in the chy-
lomicron can be taken up by adipose tissue and skeletal
muscle [4]. Once remnant chylomicrons reach the liver,
a specific carrier protein, the vitamin D binding protein
(DBP) makes it possible for them to enter the hepatocytes
and later facilitates their transport to different tissues that
need them. Endogenously, vitamin D3 can be photosyn-
thesized in the skin.
7-Dehydrocholesterol (provitamin D3) is converted to
the previtamin D3 form (precalciferol) following its expo-
sure to ultraviolet B (UVB) radiation [1]. Subsequently, it
can suffer a thermal isomerization to vitamin D3 in the
epidermis (Fig.1). Alternatively, previtamin D3 may be
photoconverted to nonactive forms, such as tachysterol
Major forms of vitamin D
Activation of vitamin D
Photobiogenesis of vitamin D
UV light 208–310 nm
Previtamin D3
7-Dehydrocholesterol
Previtamin D3
5.9%
Liver
25(OH)D3
Kidney
Vitamin D3
94.1%
Vitamin D3
1,25-(OH)
2
D
3
Vitamin D3
Skin
Vitamin D3
Vitamin D2
HO HO
HO
HO
HO
HO
H
H
H
CH3
CH3
CH3
CH3
CH3
H H
H
CH2
CH3
CH3
CH3
CH3
CH2
CH2
CH3
CH3
CH3
CH3
CH3CH3
CH3
CH3
CH3
Fig. 1. Vitamin D forms, photobiosynthesis, and activation.

Vitamin D Actions
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and lumisterol, which may exert different biological ac-
tivities [5]. The production of vitamin D3 in the skin is
due to the extent and quality of the UVB radiation reach-
ing the dermis as well as the availability of 7-dehydrocho-
lesterol and the characteristics of the skin.
Liver and Renal Metabolism of Vitamin D to the
Active Hormonal Form
Once vitamin D enters the circulation through the skin
or from the lymph, it is cleared by the liver or storage tis-
sues within a few hours. In the liver, precalciferol is rap-
idly hydroxylated by the 25-hydroxylase, a cytochrome
P450 enzyme, (mainly the CYP2R1), which forms 25-hy-
droxyvitamin D (25(OH)2D; calcidiol), through an unreg-
ulated process [6]. Once synthesized, DBP-bound 25(OH)
D is secreted into blood and requires a renal hydroxylation
to obtain the active form 1α,25 dihydroxyvitamin D (cal-
citriol). The average plasma life of 25(OH)D is around
3weeks; this is what makes serum levels of this 25(OH)D
indicative of the body vitamin D storage and status.
When calcitriol is required due to a lack of calcium or
phosphate, 25(OH)D is 1α-hydroxylated in the kidney
forming the physiologically active form 1,25(OH)2D.
This reaction is catalyzed by the 25(OH)D 1α-hydroxylase
enzyme, which is another CYP450-dependent system
(CYP27B1) [7]. This step occurs in the mitochondria of
the proximal convoluted tubule cells, and is very tightly
regulated by blood calcium and phosphate levels through
parathyroid hormone (PTH) and the fibroblast growth
factor 23 (FGF-23) [8]. Furthermore, 1,25(OH)2D can act
as a suppressor of CYP27B1, although the mechanism is
not fully understood. Vitamin D can be stored in the adi-
pose tissue, this accumulation being higher in obese than
in normal weight subjects, but this stored vitamin D is not
readily available, since it is not released when needed [9].
Inactivation and Excretion of Vitamin D
The CYP450 24-hydroxylase is present in the proximal
convoluted tubule cells and in all target cells, expressing
the vitamin D specific receptor (VDR). Calcitriol induces
its own destruction by stimulating the 24-hydroxylase,
which is also responsible for the degradation of its precur-
sor, 25(OH)D3. Several oxidation reactions follow this
24-hydroxilation and sometimes the conjugation with
glucuronic acid, thereby forming a number of com-
pounds excreted through the bile [6]. The renal excretion
is usually very low (<5%). The DBP-vitamin D complex
may be filtrated at the glomerulus and specifically re-up-
taken in a process mediated by a DBP-specific cubilin-
megalin receptor system [10].
Regulation of Vitamin D Metabolism
Regulation of calcitriol depends on the balance be-
tween 1α-hydroxylase and 24-hydroxylase activities.
Both enzymes are rigorously regulated by serum calcium,
calcitriol, and phosphate levels. Under low serum calcium
conditions, or low levels of vitamin D, PTH secreted by
the parathyroid glands stimulates the synthesis of the
1α-hydroxylase, resulting in the increase of 1,25(OH)2D
activation [11]. PTH also inhibits 24-hydroxylase [12],
and can induce osteoclast and osteocytes synthesis of the
FGF-23, which acts by reducing the expression of renal
sodium-phosphate transporters [13]. FGF-23 can also ad-
just vitamin D homeostasis by suppressing renal expres-
sion of 1α-hydroxylase and inducing 24-hydroxylase,
thus reducing serum calcitriol levels and subsequently se-
rum calcium under hyperphosphatemia conditions [14].
Classical Action of Vitamin D: Regulation of Calcium
and Phosphate Homeostasis.
Calcitriol participates in the regulation of plasma ion-
ized calcium and phosphate levels by acting on their in-
testinal absorption, renal excretion, and calcium bone
mobilization as described below (Fig. 2). When serum
calcium levels decrease, PTH secretion is stimulated and
activates calcitriol synthesis. Both PHT and calcitriol
stimulate calcium renal reabsorption and mobilization
from bones (bone resorption).
In contrast, if serum calcium levels rise, PTH secretion
drops, leading to a decrease of calcitriol and calcium mo-
bilization. Indeed, if serum calcium levels become too
high, the parafollicular cells of the thyroid secrete calcito-
nin, which block calcium mobilization from the bone and
stimulate calcium and phosphorous excretion [15], con-
tribute to keep calcium levels within the normal range.
Calcitriol acts directly on 3 target tissues with the aim
of maintaining optimal serum calcium levels. In addition,
through VDR, calcitriol suppresses parathyroid gene ex-
pression and parathyroid cell proliferation, reinforcing
its direct action on increasing serum calcium levels [16].
The first target organ is the intestine (without PTH
mediation); here calcitriol stimulates intestinal calcium

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absorption that depends on its presence in the diet, intes-
tinal solubility, and intestinal absorption capacity, which
is the result of the balance between transcellular and para-
cellular intestinal absorption [2]. When calcium intake is
high, paracellular transport will be sufficient [17]. Trans-
cellular transport involves 3 phases: (1) entrance of cal-
cium through specific calcium channels (such as TRPV6)
present in membranes of the brush border; (2) intracel-
lular transport mediated by calbindin; and (3) calcium
active transport to the blood stream at the basolateral sur-
face mainly mediated by specific carriers [2, 14, 17].
The second organ are the kidneys; calcitriol with PTH
encourages the renal distal tubule reabsorption of calci-
um. Calcitriol influences (1) calcium entrance through
the apical membrane; (2) calbamicin-mediated calcium
diffusion; and (3) active transport thought the basolateral
membrane [18]. Vitamin D inhibits phosphate reabsorp-
tion indirectly by increasing FGF-23 osteocytes expres-
sion, and directly by inducing α-klotho (FGF-23 co-re-
ceptor) [14].
The third target tissue is the bone. Calcitriol mobilizes
calcium from bone, a process requiring PTH [19]. When
serum calcium levels decrease, PTH-dependent calcitriol
activation prompts the formation and VDR-mediated
differentiation of osteoclasts. This activation induces the
mobilization of calcium from the bone by stimulating the
secretion of the receptor activator for nuclear factor kap-
pa-B ligand, which, in turn, is responsible for osteoclas-
togenesis and bone resorption [20]. At the same time, vi-
tamin D inhibits mineralization through the increase of
pyrophosphate levels and osteopontin [21]. Calcitriol
promotes bone formation and growth, by activating
chondrocyte differentiation, and increasing serum calci-
um and phosphate levels. Thus, vitamin D deficiency re-
sults in inadequate mineralization of the skeleton, and
when low vitamin D levels are maintained, bone growth
plates cannot be mineralized due to calcium and phos-
phate depletion [22, 23].
Mechanisms of Action of Vitamin D
The mechanism of action of the calcitriol is mediated
by the VDR, which belongs to a subfamily of nuclear re-
ceptors that act as transcription factors into the target
cells after forming a heterodimer with retinoid X receptor
(RXR). Once dimerized, the complex binds to the VDR
element, in the promoter regions of target genes or at dis-
tant sites, to positively or negatively regulate their expres-
sion [24]. As the VDR has been found in virtually all cell
types [25], it may explain its multiple actions on different
tissues [26].
1,25(OH)2D3
Bone synthesis Bone resorption
+++ + +
Differentiation/
mineralization of
growth plates
Primary
chondrocytes
Hypertrophied
chondrocytes
Calcified
chondrocytes
Primary
esponge
Osteoblast
differentiation
Osteoblast
activation
Osteoblast
precursors
Osteoblast
cells
Growth
factors
cytokines
Non-mineralized
matrix
Osteocalcin/osteobindin
Osteocytes
Bone
Osteoblast
differentiation
Mineralization
Ca2+ binding
Osteoblast
Fig. 2. Vitamin D classic actions in the bone system.
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Besides 1,25(OH)2D3, the VDR-RXR dimer can asso-
ciate with other molecules as the p160 coactivators fam-
ily of steroid receptor coactivators 1, 2, and 3, that have
histone acetylase (HAT) activity, and are primary coacti-
vators that bind to the AF2 domain of liganded VDR [27].
Members of p160 family recruit proteins as secondary co-
activators, such as CBP/p300, which also have HAT activ-
ity, resulting in a multi-subunit complex that modifies
chromatin and destabilizes histone/DNA interaction
[28]. The modification of histones occurs not only by
acetylation, but also through methylation [27]. Liganded
VDR interacts with basal transcription factors (TFIIB and
several TATA DNA box binding protein-associated fac-
tors). VDR-intermediated transcription is facilitated by
the mediator, a multi-protein complex that functions
through the recruitment of RNA polymerase II and pro-
motes the formation of the preinitiation complex [29]
(Fig.3).
There is increasing evidence that specific CAAT en-
hance binding protein (C/EBP) family members may be
key mediators of 1,25(OH)2D3 action. C/EBP is induced
by 1,25(OH)2D3 in kidney and osteoblastic cells and co-
operates with 1,25(OH)2D3 and VDR in enhancing
Cyp24a1 and Bglap genes transcription [30]. C/EBP and
VDR cooperate in the transcriptional regulation of the
human antimicrobial peptide cathelicidin in lung epithe-
lial cells, and Runx2 and VDR collaborate in the tran-
scriptional regulation of mouse osteopontin in osteoblas-
tic cells [30]. C/EBP, Runx2, and VDR all contribute to
the control of matrix metalloproteinase 13 gene tran-
scription [31]. The SWI/SNF complexes contribute to
transcriptional activation by VDR. C/EBP recruits the
SWI/SNF complex to promote 1,25(OH)2D3 induction of
Cyp24a1 and Bglap transcription [32] (Fig.3).
Low-affinity nutritional VDR ligands including cur-
cumin, polyunsaturated fatty acids, and anthocyanidins
initiate VDR signaling, whereas the longevity factors res-
veratrol and sirtuin 1 potentiate VDR signaling [33]. The
result of VDR genomic interactions is the transcription
regulation of multiple genes, in many cases far from the
cis site of VDR binding. However, in a few cases, VDR can
exert a regulatory action in the absence of calcitriol.
The overarching principles of 1,25(OH)2D3-mediated
gene regulation in target cells are as follows: i) VDR-
binding sites are about 2,000–8,000; ii) active transcrip-
tion unit is the VDR/RXR heterodimer; iii) distal-bind-
ing site location is dispersed in cis-regulatory modules
(enhancers) across the genome; iv) VDR/RXR-binding
site sequence (VDR element) is mediated by classic hex-
americ half-sites (AGGTCA) separated by 3 base pairs
DBP 1,25(OH)2D3
Diffusion
Corepressor
- Corepressor+ VD3
+ Coactivator
Coactivator
Ac
Ac
Ac
Pol II
VDR
VD3
PCAF SRCs
CBP/p300
RxR
Promoter
Promoter
Receptor
binding
Dimerization
Transcription
regulation
VDRE
5’-GGGTCA-NNN-GGTCA-3’
AR
RXR
RxR VDR
VDRnuc 1,25
Fig. 3. Molecular mechanism of action of vitamin D. CBP/p300; CREB-binding protein binding protein p300,
PCAF; P300/CBP-associated factor, SRC, steroid receptor coactivators.
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and repression is mediated by divergent sites; v) DNA
mode of binding is predominantly, but not exclusively,
1,25(OH)2D3-dependent; vi) enhancers contain binding
sites for multiple transcription factors that facilitate both
independent or synergistic interaction; vii) epigenetic
enhancers signatures are defined by the dynamically reg-
ulated posttranslational histone H3 and H4 modifica-
tions and selectively regulated by 1,25(OH)2D3; viii) and
VDR-binding sites are highly dynamic, as they change
during cell differentiation, maturation, and disease acti-
vation and thus have consequential effects on gene ex-
pression [34]. Some mutations in the VDR affect severe-
ly its functionality causing rickets resistant to vitamin D,
a rare autosomic recessive disease, also known as type II
rickets. Those mutations modify the binding to VDR, the
nuclear location of the calcitriol-receptor complex, the
binding of the VDR to the cis elements, or the binding
of VDR to some coactivators.
Novel Actions of Vitamin D
Vitamin D regulates cell proliferation and differentia-
tion and has a key role in the responses of the immune
and nervous systems. In fact, observational studies sug-
gest that high serum concentrations of vitamin D protect
against cardiovascular disease (CVD), diabetes, and
colorectal cancer [35].
Evidence of extraskeletal effects of 1,25(OH)2D3 in-
cludes xenobiotic detoxification, oxidative stress reduc-
tion, neuroprotective functions, antimicrobial defense,
immunoregulation, anti-inflammatory/anticancer ac-
tions, and cardiovascular benefits [27]. The first evi-
dence of novel activities of the vitamin D hormone was
the demonstration that VDR was present in other tissues
like keratinocytes, promyelocytes, monocytes, lympho-
cytes, ovarian cells, islet cells of the pancreas, and so on.
[26].
Vitamin D and Cell Proliferation and Differentiation
Calcitriol and VDR have been shown to control the
expression of genes associated with cellular proliferation
and differentiation, suggesting a key role in cancer pre-
vention. There is some evidence that vitamin D levels
provide a protective status to lower the risk of cancer.
Some analyses on publications of colon, breast, prostate,
and ovarian cancer revealed that in numerous cases, vi-
tamin D3 levels correlated with reduced incidence of
cancer [36]. Conversely, other studies suggest no or only
weak evidence for a link between vitamin D levels and
cancer protection, and there are examples where high
vitamin D levels may actually increase risk (pancreatic
cancer) [37].
Preclinical studies show that calcitriol and its analogs
have antitumor effects in vitro and in vivo through mul-
tiple mechanisms including the induction of cell cycle ar-
rest, apoptosis, differentiation, and the suppression of in-
flammation, angiogenesis, invasion, and metastasis [38].
The first demonstration that vitamin D was related to
the terminal differentiation of promyelocytes to mono-
cytes was reported in 1981 [39]. Recently, calcitriol and
several structurally related members of the vitamin D
class of seco-steroids have demonstrated the ability to
regulate the hedgehog (Hh) signaling pathway, respon-
sible of tissue differentiation during embryogenesis and
maintenance of stem cell populations in certain adult tis-
sues.
In fact, dysregulation of Hh signaling results in its con-
stitutive activation and uncontrolled cellular prolifera-
tion and multiple mechanisms through which aberrantly
activated Hh signaling contributes to tumor formation,
growth, and metastasis [40]. Cross talk mechanisms be-
tween vitamin D/VDR signaling and the Hh pathway
have not been well defined; however, evidence suggests
that their interactions may play an important physiologi-
cal role, primarily in proper skin homeostasis and the on-
cogenic development of basal-cell cancer, which is the
most common type of skin cancer. These mechanisms in-
clude the transcriptional control of Hh pathway compo-
nents by VDR as well as the ability of vitamin D ligands
to directly modulate Hh pathway target genes [40]. To
maintain tight control over calcitriol-mediated differen-
tiation, keratinocytes are capable of expressing all the en-
zymatic machinery necessary to produce and metabolize
calcitriol. The levels of active CYP27A1 and CYP27B1 in
keratinocytes are controlled by multiple factors including
calcium levels, calcitriol concentration, UVB radiation,
and stage of cellular differentiation, suggesting that the
levels of calcitriol produced are tightly regulated at mul-
tiple stages [41].
Multiple studies have demonstrated the chemo-pre-
ventative and chemotherapeutic properties of both cal-
citriol and VDR in skin. Prolonged UVB radiation dam-
ages keratinocyte DNA, primarily through the formation
of mutagenic cyclobutane pyrimidine dimers (CPDs).
Direct topical administration of calcitriol or its analogues
protected against CPD formation and increased CPD
clearance [42].

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Vitamin D and the Immune System
1,25(OH)2D3 has important immunomodulatory ac-
tions, namely, the enhancement of the innate immune
system and inhibition of the adaptative immune respons-
es, associated with an increased synthesis of interleukin
(IL)-4 by T helper (Th)-2 lymphocytes and the upregula-
tion of regulatory T lymphocytes (T-reg). In fact, differ-
ent types of immune cells, for example, dendritic cells
(DC), macrophages, and T and B lymphocytes express
VDR and most of them are able to synthesize calcitriol
through an independent regulation pathway responding
to a number of proinflammatory agents as bacterial lipo-
polysaccharide and tumor necrosis factor alpha (TNF-α)
[24].
Macrophages-derived cytokines promote Th differ-
entiation to Th0 cells. Later, with the cooperation
ofsome costimulatory exogenous cytokines produced
by a number of antigen presenting cells (APC), name-
ly,macrophages and DC, Th0 differentiate to Th1 or
Th2 cells, which in turn regulates cell and antibody
immune responses. Calcitriol can regulate the im-
muneresponses in secondary lymphoid organs as well
as in target organs through a number of mechanisms
(Fig.4).
Regulation of the Innate Immune Response by DC and
Macrophages
Calcitriol increases the defense capacity of macro-
phages inducing their differentiation, phagocytic capac-
ity, and antimicrobial activity (increasing the expression
of cathelicidins). Moreover, calcitriol inhibits the prolif-
eration of monocytes, and promotes the differentiation of
monocytes to macrophages, these effects being mediated
by the upregulation of Fc surface cell receptors and by an
increase in cell respiration. In addition, calcitriol inhibits
DC proliferation, maturation, as well as their immuno-
stimulatory properties leading to the induction of T-reg
cells. Consequently, vitamin D deficiency results in a less
tolerogenic status to foreign antigens [26, 27].
Inhibition of the Pro-Inflammatory Response of APC
Calcitriol inhibits the expression of APC cytokines,
namely, IL-1, IL-6, IL-12, and TNF-α and decreases the
expression of a set of major histocompatibility complex
class II cell surface proteins in macrophages, and the de-
velopment of proinflammatory Th1 and Th17 cells, while
inducing T-reg and Th2 cells, which in turn downregulate
the activity of Th1. Thus, calcitriol inhibits the produc-
tion of IL-12 and stimulates the production of IL-10,
while downregulating the expression of some costimula-
Adaptative immunity
Macrophage or keratinocyte
Suppression of TH
Inflammation and
autoimmunity
TH
Bcell
Tcell
Tcell
TREG
TREG
CD4
DC
TH17
TH2
TH1
TH2TH17
TH1
TH1 cytokines and
immunoglobulins
TH1 cytokines
TLR
Innate immunity
Innate immunity
Cathelicidin
Calcitriol
H
HO
OH
H
H
HO
Lipopeptide
TLR
VDR
CYP27B1 +
+
–
DC maduration
Cytokines
TLR
Antigen presentation
Monocyte
MØ differentiation
Bacterial killing
Macrophage
Pathogen
Calcidiol
CYP2761
Fig. 4. Vitamin D effects on innate and adaptative immunity. CYP, cytochrome; MØ, macrophage; TH, T-helper
cell; TLR, toll-like receptor; TREG, T regulatory cell, VDR, vitamin D receptor.
Color version available online

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tory molecules, for example, clusters of differentiation
(CD) CD40, CD80, and CD86, required for the activation
of DC and other APC, leading to Th1 inhibition. Addi-
tionally, calcitriol acts directly on T cells inhibiting the
secretion of IL-2, a cytokine essential for lymphocyte
clonal expansion, and interferon gamma [26, 27].
Calcitriol also inhibits B cell differentiation and anti-
body production. Additionally, it inhibits the apoptosis
of enterocytes and promotes the synthesis of antimicro-
bial peptides, and reduces the proliferation of keratino-
cytes in psoriasis, favoring cell differentiation in both cas-
es [26, 27].
Vitamin D and CVD
Experimental studies have established that calcitriol
and VDR are critical regulators of the structure and func-
tion of the heart. In addition, clinical studies have associ-
ated vitamin D deficiency with CVD. Emerging evidence
demonstrates that calcitriol is highly involved in CVD-
related signaling pathways, particularly the Wnt signaling
pathway. Addition of calcitriol to cardiomyocyte cells
demonstrated the (i) inhibition of cell proliferation with-
out promoting apoptosis; (ii) decreased expression of
genes related to the regulation of the cell cycle; (iii) pro-
motion of the formation of cardiomyotubes; (iv) induced
expression of casein kinase-1-α1, a negative regulator of
the canonical Wnt signaling pathway; and (v) increased
expression of noncanonical Wnt11, which has been rec-
ognized to induce cardiac differentiation during embry-
onic development and in adult cells [43].
Neuroprotective Effects of Vitamin D
Vitamin D metabolites naturally pass through the
blood-brain barrier, giving them access to neuronal and
glial cells. Therefore, a number of roles for vitamin D have
been observed in various neurological/neuromuscular
disorders [44]. It has also been proposed that microglia
within the central nervous system can generate calcitriol
in situ and this might represent an antitumor response.
Calcitriol can inhibit the synthesis of inducible nitric ox-
ide synthase, leading to upregulation of glutathione; thus
it could play a role in neuroprotection or neuromodula-
tion [34].
There is widespread expression of the VDR in the
brain of adult rodents, with high levels found in sensory,
motor, and limbic systems, suggesting a role for vitamin
D throughout life. Expression of functional VDRs within
both neurons and glia of the adult hippocampus provide
further evidence for vitamin D’s importance in the adult
central nervous system. In the human brain, both VDR
and 1α-hydroxylase, the enzymes required for calcitriol
production, have been observed to be in high levels in the
substantia nigra, suggesting a potential link between this
vitamin and the dopamine neuron population linked
with Parkinson’s disease [26, 34].
Antiaging Activity of Vitamin D
Many of the health span advantages conferred by
1,25(OH)2D3 are related to its induction of α-klotho, a
renal hormone that is an antiaging enzyme/coreceptor
that protects against skin atrophy, osteopenia, hyper-
phosphatemia, endothelial dysfunction, cognitive de-
fects, neurodegenerative disorders, and impaired hearing
[33]. Together, 1,25(OH)2D3 and α-klotho maintain the
molecular signaling systems that promote growth (p21),
development (Wnt), antioxidation (Nrf2/FOXO), and
homeostasis (FGF-23) in tissues crucial for normal phys-
iology, while simultaneously guarding against malignan-
cy and degeneration [45]. Hence, VDR liganded to
1,25(OH)2D3 regulate the expression of set of genes re-
lated to health span, with the α-klotho target playing a key
role in the facilitation of health span by delaying the
chronic diseases of aging.
Disclosure Statement
The authors declare no conflicts of interest related to the pres-
ent article.
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