Joint Bone Spine 77 (2010) 552–557

Review

Vitamin D and inflammation

Xavier Guillot a,b,∗ , Luca Semerano a,b , Nathalie Saidenberg-Kermanac’h a,b , Géraldine Falgarone a,b ,
Marie-Christophe Boissier a,b
a
EA4222, Li2P, PRES Paris-Cité, université Paris 13, 93000 Bobigny, France
b
Service de rhumatologie, hôpital Avicenne, CHU Avicenne, AP–HP, 125, rue de Stalingrad, 93009 Bobigny cedex, France

a r t i c l e i n f o a b s t r a c t

Article history: Calcitriol, or 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3) is a well-known endocrine regulator of calcium
Accepted 7 September 2010 homeostasis. More recently, local calcitriol production by immune cells was shown to exert autocrine
Available online 9 November 2010
or paracrine immunomodulating effects. Immune cells that produce calcitriol also express the vitamin
D receptor (VDR) and the enzymes needed to metabolize vitamin D3 (1␣-, 25-, and 24-hydroxylases).
Keywords: Studies of animal models and cell cultures showed both direct and indirect immunomodulating effects
1,25 dihydroxyvitamin D3
involving the T cells, B cells, and antigen-presenting cells (dendritic cells and macrophages) and affecting
Vitamin D receptor
both innate and adaptive immune responses. The overall effect is a switch from the Th1/Th17 response to
1␣-hydroxylase
25-hydroxylase the Th2/Treg profile. The immunomodulating effects of vitamin D may explain the reported epidemiologi-
Dendritic cell cal associations between vitamin D status and a large number of autoimmune and inflammatory diseases.
Macrophage Such associations have been suggested by observational studies not only in rheumatoid arthritis, lupus,
T cell inflammatory bowel disease, and type 1 diabetes; but also in infections, malignancies, transplant rejec-
B cell tion, and cardiovascular disease. In animal models for these diseases, vitamin D supplementation has
been found to produce therapeutic effects. Thus, vitamin D is a key focus for public health efforts and
may hold promise for the treatment of dysimmune diseases.
© 2010 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

1. Introduction 2. Vitamin D metabolism and role in calcium homeostasis

Vitamin D is a secosteroid hormone produced chiefly in the skin
upon exposure to ultraviolet B radiation. Vitamin D can also be
supplied by the diet or by supplements. The crucial role for vitamin
D in calcium-phosphate homeostasis and bone metabolism is well
established. Serum vitamin D levels of at least 30 ng/ml (75 nmol/L)
are considered optimal to limit the release of parathyroid hor-
mone (PTH) and to promote the intestinal absorption of calcium
[1–3]. Recent observational studies suggest extraosseous effects
of vitamin D. Thus, vitamin D deficiency was associated with the
risk and/or severity of many diseases including cancer, cardiovas-
cular disease, sarcopenia, osteoarthritis, infections, and transplant
rejection. Vitamin D-deficient individuals were at increased risk
for autoimmune diseases such as diabetes, multiple sclerosis (MS),
inflammatory bowel disease (IBD), and connective tissue diseases
(e.g., rheumatoid arthritis [RA] and systemic lupus erythematosus
[SLE]). The presumptive extraosseous effects of vitamin D may be
largely ascribable to the immunomodulating properties of vitamin
D, whose mechanisms have been elucidated by animal studies and
cell culture experiments.
∗ Corresponding author.
E-mail address: xavier.guillot@avc.aphp.fr (X. Guillot).
Vitamin D regulates calcium homeostasis by influencing bone
turnover and interacting with the parathyroid glands, kidney, and
gastrointestinal tract. The two biologically relevant forms of vita-
min D are ergocalciferol or vitamin D2, found in a number of
plants and mushrooms, and cholecalciferol or vitamin D3. Vita-
min D3 can be ingested or produced in the skin upon exposure
to ultraviolet B radiation (which converts 7-dehydrocholesterol to
previtamin D3). In the bloodstream, vitamin D is carried by a spe-
cific binding protein (VDBP). To become biologically active, vitamin
D must first be hydroxylated at position 25, to calcidiol (25(OH)D),
a reaction that occurs chiefly in the liver. Calcidiol is the main cir-
culating form of vitamin D but is biologically inactive. The active
form is produced chiefly in the proximal tubule of the kidney by
hydroxylation at position 1 to calcitriol (1,25 dihydroxy-vitamin D
(1,25(OH)2 D)). Calcitriol acts by binding to the vitamin D recep-
tor (VDR), which is found in most cells in the body. In the small
bowel, the calcitriol-VDR interaction leads to increased expres-
sion of calcium-binding protein (Ca-BP) and of other proteins that
promote the transport of calcium from the gut lumen to the blood-
stream. Calcitriol binding to the VDR on osteoblasts stimulates
RANK-ligand expression, thereby promoting the maturation of pre-
osteoclasts to osteoclasts, which release calcium stores from bone
to maintain calcium homeostasis [1]. Vitamin D acts on its target

1297-319X/$ – see front matter © 2010 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2010.09.018
 X. Guillot et al. / Joint Bone Spine 77 (2010) 552–557 553

Table 1
Effects of 1,25(OH)2 D3 on immune cells.

Cell Effects of 1,25(OH)2 D3 References

Dendritic cells ↓ Decreased proliferation [15–20]

↓ Decreased differentiation ↓ survival ↓
maturation
↓ Decreases in CD40, CD80, CD86, MHC-2: ↓
decreased T-cell stimulation
↓ Decreased IL-12; Th1 response inhibition
indirect
↑ Increased IL-10 and Fox-P3: Treg induction
↓ Th17 cell induction
Macrophages ↓ Decreases in IL-6 and IL-23: decreased Th17 [12–14]
response
↓ Decreases in TNF and IL-1
↓ Decreased MHC-2: ↓ decreased antigen
presentation
↑ Increases in cathelicidin, phagocytosis,
hemotaxis
Fig. 1. Mechanism of action of vitamin D within the nucleus of target cells. ↑ Stimulation of response to infection
↓ Decreases in TLRs 9/4/2
T cells ↑ Increased transcription of IL-5 ± IL-4 in T [18–26]
cells as a steroid hormone, by binding to its nuclear receptor VDR. cells:
VDR then undergoes heterodimerization, usually with the retinoid ↑ Stimulation of Th2 response
X receptor (RXR), and binds to specific DNA sequences (vitamin-D ↓ Decreased Th1 cell proliferation (direct),
decreases in IL-2 and IFNy (RNA and proteins):
response elements, VDREs) located in promoter regions, thereby decreased Th1 response
controlling the transcription of target genes involved in calcium ↑ Increase in IL-10-producing Tr1 cells
metabolism (e.g., binding proteins) and in the immune response ↓ Decreased Th17 differentiation and IL-17
(Fig. 1). production Homing
↓ Decreased cytotoxicity of CD8 T cells
B cells ↓ Decreased proliferation [27]
3. Immunomodulating effects of vitamin D ↓ Decreased differentiation to plasma cells
↓ Decreased immunoglobin production
3.1. Enzyme metabolism

In addition to regulating calcium homeostasis, vitamin D has

many other metabolic effects, which were identified more recently
when researchers investigated the immunomodulating proper-
ties of vitamin D first described about 20 years ago [1,4,5–7].
Vitamin D contributes to regulate the proliferation, differentia-
tion, and function of immune cells, both directly and indirectly
(Table 1). Vitamin D can accumulate in the microenvironment
of lymphoid organs, where it exerts specific autocrine and/or
paracrine effects without inducing unwanted systemic events
(such as hypercalcemia and increased bone resorption). Activated
T cells (and probably B cells) can perform only the last vita-
min D-activating reaction, hydrolyzing 25(OH)D3 to 1,25(OH)2 D3,
whereas macrophages and some dendritic cells (DCs) have both
of the enzymes needed to convert vitamin D to 1,25(OH)2 D3. The
enzyme 1-alpha-hydroxylase has been found in macrophages and
activated DCs, where 1,25(OH)2 D3 can be produced locally, leading
to paracrine effects [7]. In contrast to renal cells, antigen-presenting
cells are not subject to negative regulation of 1-alpha-hydroxylase
by PTH or 1,25(OH)2 D3. In antigen-presenting cells, 1-alpha-
hydroxylase is induced by many factors, including interferon
gamma (IFN␥), and undergoes downregulation as the cell matures
[8].
3.2. Role and expression of the vitamin D receptor
When activated by 1,25(OH)2 D3, the VDR regulates gene expres-
sion in the vast array of tissues targeted by vitamin D. The VDR
is expressed by many types of immune cells including circulat-
ing monocytes, macrophages, DCs, and activated T cells [9]. In
knockout mice for the VDR, 1,25(OH)2 D3 can no longer induce
the differentiation of hematopoietic bone marrow progenitors to
monocytes/macrophages. However, VDR knockout mice exhibit
normal immune-cell subsets and similar rates of allogeneic and
xenogeneic graft rejection to those seen in wild-type mice [10].
VDR knockout mice with experimentally induced asthma have no
airway inflammation, circulating eosinophilia, or bronchial hyper-
reactivity, despite high levels of IgE and Th2 cytokines. Thus,
vitamin D may play a key role in the allergic response [11].
3.3. Effects on macrophages
Macrophages and DCs are regulated by 1,25(OH)2 D3, which
therefore plays a crucial role in innate immune responses.
Thus, 1,25(OH)2 D3 promotes monocyte-to-macrophage differ-
entiation, stimulates macrophages to produce the immunosup-
pressant prostaglandin E2, and downregulates the expression
of granulocyte-macrophage colony-stimulating factor. In addi-
tion, 1,25(OH)2 D3 diminishes the production by macrophages
of proinflammatory cytokines and chemokines. Vitamin D defi-
ciency impairs macrophage maturation and the production of
macrophage-specific membrane antigens, lysosomal acid phos-
phatase, and hydrogen peroxide required for antimicrobial activity.
Adding 1,25(OH)2 D3 increases the expression of membrane
markers, enzymes, and free oxygen radicals and enhances chemo-
taxis and phagocytosis [12]. Activated macrophages produce
1,25(OH)2 D3 in response to interferon ␥ (IFN␥) and activation of the
toll-like receptors (TLRs). Adding 100 nM of 1,25(OH)2 D3 to human
monocyte cultures inhibits the expression of the innate-immunity
receptors TLR2, TLR4, and TLR9 and alters the TLR9-dependent
production of IL-6 [13]. Other effects of 1,25(OH)2 D3, in contrast,
stimulate innate immune responses: thus, 1,25(OH)2 D3 downreg-
ulates the expression of class 2 major histocompatibility complex
(MHC) antigens at the cell surface and induces the production of
cathelicidin, a peptide involved in the antimicrobial response. In
addition, 1,25(OH)2 D3 can impair the antigen-presenting function
of macrophages by downregulating the membrane expression of
class 2 MHC molecules [14].
554 X. Guillot et al. / Joint Bone Spine 77 (2010) 552–557

3.4. Effects on dendritic cells

The proliferation and differentiation of DCs are diminished

by 1,25(OH)2 D3, which also inhibits the differentiation of mono-
cytes to DCs and the differentiation, maturation, and survival of
DCs, thus decreasing T-cell stimulation by DCs. Another effect of
1,25(OH)2 D3 is indirect inhibition of the Th1 response via inhibi-
tion of IL-12 by DCs. This inhibitory effect involves direct interaction
of 1,25(OH)2 D3 with the VDR and NFkappaB, which interferes
with IL-12 gene transcription [15]. In addition to inhibiting IL-
12, 1,25(OH)2 D3 increases IL-10 production by DCs. The net result
is a decrease in the Th1 response and probably the induction
of type 1 regulatory cells (Tr1) that produce IL-10. By acting on
co-stimulation molecules, 1,25(OH)2 D3 affects T-cell/DC interac-
tions, diminishing the production of proinflammatory cytokines
(e.g., IL-1 and TNF␣) and the membrane expression of the class
2 MHC molecules CD40, CD80, and CD86. The result is decreased
production of IL-2 and IFN␥ and increased production of IL-10 Fig. 2. Effects of vitamin D on immune cells.

and TGF␤ [16–17]. Downregulation of CD40, CD80, and CD86 in

antigen-presenting cells (including DCs) diminishes T-cell activa-
tion. In addition, 1,25(OH)2 D3 can promote the induction by DCs of
CD4+CD25+ regulatory T cells (Treg) [18]. In a murine colitis model,
1,25(OH)2 D3 increased the expression of Fox2 and IL-10, two cru-
cial factors for Treg induction [19]. This induction of tolerogenic
DCs and Treg decreased the risk of rejection in a murine organ
transplantation model [20].
3.5. Effects on T cells
Vitamin D exerts direct effects on T and B cells and modifies
their response to activation, thereby playing a key role in adap-
tive immune responses. Quiescent CD4+ T cells express the VDR
at a low level, and their activation is associated with a five-fold
increase in the VDR expression level. The effect of 1,25(OH)2 D3
on T cells is both indirect, via the DCs, and direct, via inhibition
of T-cell proliferation. To date, 102 genes targeted by 1,25(OH)2 D3
have been identified in CD4+ T cells [21]. Furthermore, 1,25(OH)2 D3
affects T-cell differentiation, inhibiting the Th1 response (charac-
terized by cell proliferation, transcription of the genes encoding
IFN␥ and IL-2, and protein expression of these genes) and stim-
ulating the Th2 response (IL-4, IL-5, and IL-10) by increasing the
production of IL-5 and IL-10, as well as indirectly by diminishing
the production of IFN␥ [22]. In combination with glucocorticoids,
1,25(OH)2 D3 induces Tr1 cells that produce IL-10 and suppress
the immune response. This mechanism may contribute to explain
the beneficial effects of vitamin D in autoimmune disease mod-
els [23]. In VDR knockout mice, CD4+ T cells produce more IFN␥
and less IL-2, IL-4, and IL-5 compared to wild-type mice [24].
In addition, 1,25(OH)2 D3 indirectly inhibits the Th1 response by
inhibiting IL-2 production by antigen-presenting cells and inhibits
the Th17 response by blocking the production of IL-6 and IL-23
[19]. In cell culture experiments, 1,25(OH)2 D3 induces Treg in the
presence of IL-2, by upregulating the transcription of Fox-P3 and
CTLA4 [25]. T-cell homing is affected by 1,25(OH)2 D3. In humans,
for instance, 1,25(OH)2 D3 acts synergistically with IL-12 to induce
the expression of the skin homing marker CCR10 at the keratinocyte
surface. Keratinocytes express the CCR10 ligand CCL27, a T-cell
homing chemokine. Thus, 1,25(OH)2 D3 may promote T-cell circu-
lation or retention within the epidermis [7]. Finally, the cytotoxic
response mediated by CD8+ T cells is inhibited by 1,25(OH)2 D3 [26].
Overall, 1,25(OH)2 D3 inhibits the Th1 and Th17 proinflammatory
responses and promotes the Th2, Treg, and Tr1 immunomodulat-
ing responses. The net result is downregulation of the effector T-cell
immune response (Fig. 2).
3.6. Effects on B cells
Effects of 1,25(OH)2 D3 on B cells include inhibition of B-cell
proliferation, differentiation to plasma cells, and production of
immunoglobulins, most notably in patients with SLE [27]. Many
studies have found significantly lower serum 25(OH)D levels in
patients with autoimmune diseases compared to healthy controls.
Vitamin D supplementation has been reported to prevent autoim-

Table 2
Effects of vitamin D on autoimmune diseases.

Vitamin D deficiency Therapeutic effect Animal models Effect of supplementation in these models References
(supplementation)

RA More common Pain Collagen-induced Prevention [28–38]

Disease prevalence increases with latitude CRP arthritis (mice) Decreased arthritis
Correlates with disease activity (DAS28 and
CRP)
SLE More common MRL/lpr mice Increased survival [44–50]
Correlates with disease activity (SLEDAI) Decreased proteinuria
Type 1 diabetes More common Prevention NOD mice Halts progression [51–53]
Induces Treg
Decreases IL-12
MS Disease prevalence increases with latitude Prevention EAE (mice) Prevention and treatment [54–59]
Correlates with risk of developing MS Decreased relapse rate IL-10-dependent
IBD More common Decreased relapse rate IL-10 knockout Prevention [39–43]
Disease prevalence increases with latitude mice Weight gain and increased survival
Correlates with relapse rate Efficacy increased by concomitant calcium

RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; MS: multiple sclerosis; IBD: inflammatory bowel disease; DAS28: Disease Activity Score, 28 joints; CRP: serum
C-reactive protein level; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; EAE: experimental autoimmune encephalomyelitis; IL: interleukin.
 X. Guillot et al. / Joint Bone Spine 77 (2010) 552–557
mune diseases or to decrease their severity (Table 2), and vitamin
D deficiency has been associated with many autoimmune diseases
[1].
4. Rheumatoid arthritis
The prevalence of vitamin D deficiency is increased among
patients with RA compared to the general population [28]. How-
ever, whether vitamin D deficiency is a cause or a consequence of
the diseases remains unclear. In the Iowa Women’s Health Study,
a higher vitamin D intake as assessed using a food frequency ques-
tionnaire was associated with a lower risk of RA [29]. However, a
serum-bank case-control study from The Netherlands found no cor-
relation between serum 25(OH)D3 levels and the development of
RA [30]. In an evaluation of the Nurse’s Health Study cohort includ-
ing 190 patients with SLE and 722 with RA, there was no correlation
between vitamin D intake estimated from semi-quantitative food
frequency questionnaires and the risk of SLE or RA [31]. In RA
patients, serum 25(OH)D3 levels correlated negatively with dis-
ease activity [32]. In interventional trials, supplementation with
1 ␮g 1,25(OH)2 D3 had no significant effect [33], whereas higher
doses were associated with decreased pain and significant declines
in C-reactive protein levels [34].
In the murine model of collagen-induced arthritis, supplemen-
tation with 1,25(OH)2 D3 prevents arthritis development and halts
arthritis progression [35–36]. In human chondrocyte cultures, vita-
min D metabolites act via the VDR to regulate the transcription of
numerous genes involved in chondrocyte metabolism. The results
of this regulatory effect include modulation of proteoglycan and
collagen synthesis and of the expression of specific matrix met-
alloproteinases. The VDR is expressed in the human rheumatoid
synovium, at the junction between the cartilage and the pannus,
by macrophages, chondrocytes, and synoviocytes; in contrast, VDR
expression is not found in controls [37]. Joint fluid macrophages
can produce 1,25(OH)2 D3. High levels of vitamin D metabolites
have been found in joint fluid from patients with arthritis [38], sug-
gesting a pathophysiological role for 1,25(OH)2 D3 in rheumatoid
lesions.
5. Inflammatory bowel disease
The prevalence of IBD is higher in areas that receive less sunlight,
such as the northernmost parts of Europe and America [39]. Patients
with IBD have lower serum 25(OH)D3 levels than do healthy con-
trols [40]. This characteristic may be related to a combination of
factors including decreased intestinal absorption, lower dietary
intakes, and limited sun exposure. Patients with newly diagnosed
IBD also have low serum 25(OH)D3 levels compared to controls
[41]. In a recent double-blind randomized controlled trial in 108
patients with Crohn’s disease, daily oral supplementation with
1200 IU/d of 25(OH)D3 increased the mean serum 25(OH)D3 levels
from 69 to 96 nmol/L and diminished the relapse rates over the 1-
year follow-up (13% vs. 29%; P = 0.06) compared to the placebo [42].
In IL-10 knockout mice, vitamin D deficiency was associated with
accelerated bowel inflammation, whereas vitamin D3 supplemen-
tation had therapeutic effects [24]. In mice with experimentally
induced colitis, a low calcemic vitamin D analog exhibited both
preventive and therapeutic effects [43].
6. Systemic lupus erythematosus
In the US, African Americans have a three-fold higher incidence
of SLE with earlier disease onset and higher morbidity and mor-
tality rates compared to Caucasians [44]. A genetic factor does not
seem involved, as SLE is rare in West Africa. The most likely expla-
555
nation is vitamin D deficiency due to limited sunlight exposure
and decreased penetration of ultraviolet B radiation through darker
skin. Vitamin D deficiency is common in patients with SLE, regard-
less of disease duration, but may be a consequence of the disease,
related for instance to photosensitivity requiring protection from
sunlight [45]. A cross-sectional study found no significant differ-
ence in serum 25(OH)D3 levels between 25 women with SLE and
25 women with fibromyalgia [46]. Serum 25(OH)D3 levels may cor-
relate negatively with disease activity [47]. In one study, serum
25(OH)D3 levels were lower in patients with undifferentiated con-
nective tissue disease than in controls [48]. Vitamin D deficiency
may be involved in the subsequent development in these patients of
differentiated connective tissue diseases (RA, Sjögren’s syndrome,
SLE, overlap syndromes, systemic vasculitides, and antiphospho-
lipid syndrome). In addition, involvement of the skin and pleural
membrane correlated negatively with serum 25(OH)D3 levels in
this study [48]. In murine models of SLE, beneficial effects of vitamin
D supplementation include decreased proteinuria and increased
survival times [49–50].
7. Diabetes and multiple sclerosis
Serum 25(OH)D3 levels are often lower in patients with type 1
diabetes than in healthy controls. Vitamin D supplementation dur-
ing childhood is associated with a decreased risk of type 1 diabetes.
Thus, in a 30-year birth-cohort study (1966–1997), the relative risk
of type 1 diabetes was 0.12 in the individuals who had received
2000 IU/day of supplemental vitamin D during their first year of
life, compared to those given no vitamin D supplements [51]. Indi-
viduals with suspected rickets during the first year of life had a
relative risk of 3.0 [51]. In mice with diabetes (NOD), administra-
tion of a 1,25(OH)2 D3 analog diminished the expressions of IL-12
and IFN␥, prevented DC maturation and pancreatic islet infiltration
by Th1 cells, and halted disease progression [52]. Treg cells were
probably involved in this effect, as they were found in increased
numbers in the nodes draining the pancreas [53]. The prevalence
of MS varies considerably with latitude, from 1–2/100,000 near the
equator to more than 200/100,000 north of the 50th parallel [54].
Among patients with MS, 77% had serum 25(OH)D3 levels lower
than 50 nmol/L [55]. In a study of seven million US military per-
sonnel, the risk of MS correlated negatively with serum 25(OH)D3
levels in Caucasians. However, these individuals had severe vita-
min D deficiency, with serum 25(OH)D3 levels lower than 10 ng/ml,
whereas the optimal level is estimated to be 90–100 nmol/L [56]
Vitamin D supplementation decreases the risk of MS and, in MS
patients, diminishes the relapse rate [57]. In the experimental
autoimmune encephalitis murine model of MS, vitamin D sup-
plementation exerts preventive and therapeutic effects that are
mediated by IL-10 [58].
8. Therapeutic implications
To ensure optimal bone health, the serum 25(OH)D3 level
should be at least 30 ng/ml (75 nmol/L), with the ideal range being
estimated at 30–60 ng/ml. Vitamin D poisoning occurs at levels
greater than 150 ng/ml [1]. Only fragmentary information is avail-
able on the serum 25(OH)D3 level required for vitamin D to exert
immunomodulating effects. In one study, the risk of MS decreased
by 41% for each 20 ng/ml increase in serum 25(OH)D3, starting at
a threshold level of about 24 ng/ml (60 nmol/L) [56]. When serum
25(OH)D levels fall below 20 ng/ml (50 nmol/L), human monocytes
and macrophages are unable to initiate some of the innate immune
responses. This fact may explain the excess risk of tuberculosis in
populations with vitamin D deficiency such as African-Americans
[14]. No serum 25(OH)D threshold has been documented for RA.
556 X. Guillot et al. / Joint Bone Spine 77 (2010) 552–557
However, in one study, each 10 ng/ml increase in serum 25(OH)D
was associated with a 0.3-point decrease in mean DAS28 and a 25%
decrease in serum C-reactive protein [32].
The wide variety of vitamin D effects on the immune response
suggests that vitamin D may hold therapeutic promise in many
autoimmune diseases. Conceivably, increasing the vitamin D intake
may diminish the incidence and severity of several diseases such
as RA, type 1 diabetes, IBD, and MS. Obtaining immunomodulat-
ing effects in vitro requires local concentrations of 1,25(OH)2 D3 of
about 10−10 M. To obtain such concentrations in vivo requires sup-
raphysiological doses of vitamin D3, which are associated with an
unacceptable risk of hypercalcemia. Therefore, vitamin D analogs
that do not induce hypercalcemia have been developed. Another
option may be to combine vitamin D3 with immunomodulators
such as cyclosporine or bisphosphonates [43]. In vivo studies of
murine models suggest that not only vitamin D, but also an ade-
quate intake of dietary calcium, contribute to modulate the immune
response in the gastrointestinal tract and central nervous system.
Concomitant calcium supplementation enhances the ability of vita-
min D to prevent IBD and MS [59].
Vitamin D exerts immunomodulating effects that may hold
promise in many diseases characterized by inflammation, including
autoimmune diseases, infections, malignancies, and cardiovascu-
lar diseases. These immunomodulating effects may be related to
anti-Th1 and anti-Th17 effects, pro-Th2 effects, and induction of
Treg and Tr1 cells [60]. Randomized controlled trials are under
way to determine the best treatment modalities (dosage, target lev-
els, pharmacological forms, and desirability of concomitant calcium
supplementation).
Conflict of interest statement
The authors declare no conflicts of interest.
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