Vitamin D and the immune system: role in protection against

bacterial infection
Daniel D. Bikle
Veterans Affairs Medical Center, San Francisco,
California, USA
Correspondence to Daniel D. Bikle, Veterans Affairs
Medical Center (111N), 4150 Clement St,
San Francisco, CA 94121, USA
E-mail: Daniel.bikle@ucsf.edu
Current Opinion in Nephrology and
Hypertension 2008, 17:348–352
Purpose of review
The role of vitamin D extends well beyond that of regulating calcium homeostasis.
One of these areas is immune function. Immunity is both adaptive and innate, and
vitamin D signaling is operative in both. This review will examine these actions of
vitamin D, in particular the role of vitamin D in host defense against infection.
Recent findings
This review will consider two examples of vitamin D-regulated innate immunity that have
been recently explored: the role of vitamin D signaling within macrophages to enable
them to respond to and kill Mycobacterium tuberculosis organisms, and the role of
vitamin D signaling in the keratinocytes of the epidermis to enable them to respond to
disruption of their barrier function. Potential application to periodontal disease will then
be considered.
Summary
Both adaptive and innate immune processes are two edged: beneficial and harmful.
Although suppression of adaptive immunity may be beneficial in a number of self-
destructive diseases, such suppression may predispose to infection. Enhancement of
innate immunity is clearly beneficial in diseases like tuberculosis, but potentiation of
proinflammatory processes can increase tissue destruction as in bone loss in
periodontal disease. The balance, however, favors adequate vitamin D nutrition in host
defense against infection.

Keywords
adaptive immunity, innate immunity, keratinocyte, macrophage, periodontium, vitamin D

Curr Opin Nephrol Hypertens 17:348–352

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1062-4821

bat the source of the antigen presented to them by cells

Introduction
The potential role for vitamin D and its active metabolite
1,25(OH)2D3 in modulating the immune response was first
appreciated 25 years ago with three important discoveries:
the presence of vitamin D receptors (VDRs) in activated
human inflammatory cells [1], the ability of 1,25(OH)2D3
to inhibit T cell proliferation [2], and the ability of disease-
activated macrophages to produce 1,25(OH)2D3 [3]. The
enzyme responsible for 1,25(OH)2D3 production in macro-
phages and subsequently also identified in dendritic cells
is the same enzyme as exists for that purpose in the kidney
(CYP27B1). Unlike that in the kidney, however, this
enzyme in macrophages and dendritic cells like that in
keratinocytes [4,5] is stimulated by cytokines but not by
parathyroid hormone (PTH) and is not directly feedback-
inhibited by its product [6,7]. We now know that vitamin D
and CYP27B1 play important roles in both innate and
adaptive immunity.
The adaptive immune response is generally defined by T
and B lymphocytes and their ability to produce cytokines
and immunoglobulins, respectively, to specifically com-
such as macrophages and dendritic cells. Vitamin D
exerts an inhibitory action on the adaptive immune
system. In particular, 1,25(OH)2D3 suppresses prolifer-
ation and immunoglobulin production and retards the
differentiation of B cell precursors into plasma cells [8
].
As noted above 1,25(OH)2D3 inhibits T cell proliferation
[2], in particular the Th1 cells capable of producing
interferon (IFN)-g and interleukin (IL)-2 and activating
macrophages [9]. These actions prevent further antigen
presentation to and recruitment of T lymphocytes (role of
IFN-g), and T lymphocyte proliferation (role of IL-2). In
contrast IL-4, IL-5, and IL-10 production can be
increased [10], shifting the balance to a Th2 cell pheno-
type. T regulatory (Treg) cells are also increased by
1,25(OH)2D3 [11] as shown by increased FoxP3 expres-
sion and IL-10 production [12
]. The IL-10 so produced
is one means by which CD4þ/CD25þ Treg cells block
Th1 development. At least in part these actions on T cell
differentiation stem from actions of 1,25(OH)2D3 on
dendritic cells. 1,25(OH)2D3 decreases expression of
the costimulatory molecules CD40, CD80, CD86 in
dendritic cells and decreases their secretion of IL-12, a

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cytokine critical for Th1 development [13]. These
changes markedly reduce the antigen-presenting
capability of these cells. The impact of 1,25(OH)2D3
on Th17 development and function was more recently
discovered, and many of the salubrious effects of
1,25(OH)2D3 on various autoimmune diseases previously
ascribed to inhibition of Th1 development and function
are now being ascribed at least in part to inhibition of
Th17 development and function. In particular,
1,25(OH)2D3 not only inhibits IL-12 secretion, important
for Th1 development, but also IL-23 and IL-6 production
important for Th17 development and function [12
].
Consequently, IL-17 secretion is also inhibited [12
].
Th17 cells have recently been shown to play important
roles in psoriasis [14] and experimental colitis [12
],
conditions that respond to 1,25(OH)2D3 and its analogs.
The ability of 1,25(OH)2D3 to suppress the adaptive
immune system appears to be beneficial for a number
of conditions in which the immune system is directed at
self, such as autoimmunity. In a number of experimental
models [15,16] including inflammatory arthritis, auto-
immune diabetes (e.g. NOD mice), experimental allergic
encephalitis (a model for multiple sclerosis), and inflam-
matory bowel disease 1,25(OH)2D3 administration has
prevented or treated the disease process. Although
prospective, randomized, placebo-controlled trials in
humans have not yet been performed, epidemiologic
and case–control studies indicate that a number of these
diseases in humans are also favorably affected by ade-
quate vitamin D levels. Suppression of the adaptive
immune system, however, may not be without a price.
Several recent publications have demonstrated that for
some infections, including Leishmania major [17
] and
toxoplasmosis [18], 1,25(OH)2D3 promoted the infection
[18] while the mouse null for VDR was protected [17
].
Innate immune responses involve the activation of
Toll-like receptors (TLRs) in polymorphonuclear cells
(PMNs), monocytes and macrophages as well as a num-
ber of epithelial cells including those of the epidermis,
gingiva, intestine, vagina, bladder and lungs. TLRs are an
extended family of host noncatalytic transmembrane
pathogen-recognition receptors that interact with specific
membrane patterns (PAMP) shed by infectious agents
that trigger the innate immune response in the host [19
].
Activation of TLRs leads to the induction of antimicro-
bial peptides and reactive oxygen species, which kill the
organism. Among those antimicrobial peptides is cathe-
licidin. The expression of this antimicrobial peptide is
induced by 1,25(OH)2D3 in both myeloid and epithelial
cells [20,21]. Both macrophages [3] and epithelial cells
[22] are capable of responding to and producing
1,25(OH)2D3 (i.e. they both have VDR and the enzyme
CYP27B1 which produces 1,25(OH)2D3). Stimulation of
TLR2 by a microbial lipopeptide in macrophages [23] or
stimulation of TLR2 in keratinocytes by wounding the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Vitamin D and the immune system Bikle 349
epidermis [9] results in increased expression of
CYP27B1, which in the presence of adequate substrate
(25(OH)D) stimulates the expression of cathelicidin.
Lack of substrate (25(OH)D) or lack of the VDR blunts
the ability of these cells to respond to a challenge with
respect to cathelicidin production [21,23,24

]. As men-
tioned, the innate immune system is widely distributed,
and operates not only in cells within the lymphopoietic
system but within epithelia such as the epidermis, gastro-
intestinal epithelium, periodontal apparatus, bladder,
vagina, and lung: those tissues which face the outside
and an infectious organism-filled environment. Epide-
miologic evidence suggests that vitamin D deficiency is
associated with increased risk of infection in a number of
these tissues [25].
For this review I will focus on the innate immune system
in two distinct tissues where vitamin D regulation clearly
plays a role in the host defense against infection, namely
macrophages and the epidermis. I will then address
immune regulation in the periodontium where the evi-
dence for vitamin D regulation is much less developed
but which serves as a good example of the interaction
between the adaptive and innate immune systems in
protection against infection and a ripe area for future
research in vitamin D regulation of the infectious process.
Vitamin D regulation of the innate immune
system in macrophages
The importance of adequate vitamin D nutrition for
resistance to infection has long been appreciated but
poorly understood. This has been especially true for
tuberculosis. Indeed, prior to the development of specific
drugs for the treatment of tuberculosis, getting out of the
city into fresh air and sunlight was the treatment of
choice. In a recent survey of patients with tuberculosis
in London [26] 56% had undetectable 25(OH)D levels,
and an additional 20% had detectable levels but below
9 ng/ml (22 nM). In 1986 Rook et al. [27] demonstrated
that 1,25(OH)2D could inhibit the growth of Mycobacter-
ium tuberculosis. The mechanism for this remained
unclear until the publication of a study by Liu et al.
[23]. They observed that activation of the Toll-like
receptor TLR2/1 by a lipoprotein extracted from
M. tuberculosis reduced the viability of intracellular
M. tuberculosis in human monocytes and macrophages
concomitant with increased expression of the VDR and
of CYP27B1 (the enzyme that produces 1,25(OH)2D3) in
these cells. Killing of M. tuberculosis occurred only when
the serum in which the cells were cultured contained
adequate levels of 25(OH)D, the substrate for CYP27B1.
This provided clear evidence for the importance of
vitamin D nutrition in preventing and treating this dis-
ease, demonstrating the critical role for endogenous
production of 1,25(OH)2D3 by the macrophage to enable
 350 Mineral metabolism
its antimycobacterial capacity. Activation of TLR2/1 or
directly treating these cells with 1,25(OH)2D3 induced
the antimicrobial peptide cathelicidin, which is toxic for
M. tuberculosis. If induction of cathelicidin is blocked as
with siRNA, the ability of 1,25(OH)2D3 to enhance the
killing of M. tuberculosis is prevented [28]. Furthermore,
1,25(OH)2D3 also induces the production of reactive
oxygen species which if blocked likewise prevents
the antimycobacterial activity of 1,25(OH)2D3-treated
macrophages [29]. The murine cathelicidin gene lacks
the VDR response element in its promoter, and so would
not be expected to be induced by 1,25(OH)2D3, yet
1,25(OH)2D3 stimulates antimycobacterial activity in
murine macrophages. Murine macrophages, unlike human
macrophages, however, utilize inducible nitric oxide
synthase (iNOS) for their TLR and 1,25(OH)2D3-
mediated killing of M. tuberculosis [29,30].
Vitamin D regulation of the innate immune
system in the epidermis
Cathelicidiin expression in human epidermal keratino-
cytes is also readily induced by 1,25(OH)2D3 [21,31].
Surprisingly, similar induction of cathelicidin in colon
epithelial cells by 1,25(OH)2D3 was not found although
butyrate could lead to such induction [31]. In epidermal
keratinocytes butyrate, which by itself has little effect,
potentiates the ability of 1,25(OH)2D3 to induce cathe-
licidin [32]. Keratinocytes treated with 1,25(OH)2D3
were substantially more effective in killing Staphyococcus
aureus than were untreated keratinocytes. Similar results
had been found for the human epidermal cell line SCC25
(derived from the tongue) with respect to killing of
Escherichia coli and Pseudomonas aeruginosa [21]. Of course
when the skin is wounded, it is most susceptible to
bacterial invasion. Recent studies by Schauber et al.
[24

] demonstrated that following wounding the expres-
sion of TLR2 is increased as is the expression of its
co-receptor CD14 and cathelicidin. Concurrent expression
of CYP24A1 (25(OH)D-24 hydroxylase), a sensitive
marker of 1,25(OH)2D3 transcriptional activity, suggested
the role of 1,25(OH)2D3 in this process, and indeed
1,25(OH)2D3 was found to stimulate TLR2 and CD14
in cultured keratinocytes as well as in the epidermis when
applied topically [24

]. In macrophages (HL-60 cells)
1,25(OH)2D3 was found to induce CD14, but not TLR2
[33]. Wounding also increased the expression of CYP27B1.
This may occur as a result of increased levels of cytokines
such as tumor necrosis factor (TNF)-a and IFN-g, both of
which we [4,34] have shown stimulate 1,25(OH)2D3 pro-
duction, as well as by transforming growth factor (TGF)-b
and the TLR2 ligand Malp-2 [24

]. Mice lacking
CYP27B1 fail to respond to wounding with an increase
in CD14, and the increase in cathelicidin is blunted [24

].
As mentioned previously, unlike the human cathelicidin
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
gene, the mouse gene does not contain a vitamin D
response element, and is not induced directly by
1,25(OH)2D3. The partial inhibition of cathelicidin
expression is likely due to the decrease in CD14, which
as a coreceptor for TLR2 would be expected to minimize
the innate immune response. When the VDR or one of its
principal coactivators, SRC3, was knocked down using
siRNA technology, the ability of 1,25(OH)2D3 to induce
cathelicidin and CD14 expression in human keratinocytes
was markedly blunted [32].
Periodontal disease: potential target for
vitamin D regulation
The periodontal apparatus involves an epithelium that
attaches to teeth within alveolar bone. The protrusion of
the tooth into the oral cavity where it may be bathed with
a variety of benign and potentially pathogenic organisms
predisposes this apparatus to infection. The gingival
epithelium that attaches to the tooth is called the junc-
tional epithelium. Unlike the more differentiated cells
of the rest of the gingival epithelium, the junctional
epithelium is composed of less differentiated cells with
less tight intercellular junctions, making this region
susceptible to the invasion of these pathogens. Bacterial
accumulations or dental plaque form on the teeth and
give rise to the inflammatory process resulting in period-
ontal disease. Chronic and progressive infection results in
alveolar bone destruction, which may progress to loss of
teeth. The most prevalent form of periodontal disease is
gingivitis, characterized by inflammation of the gums
with easy bleeding. This affects 75% of adults in the
USA [35], but more severe forms of the disease are also
common. A variety of conditions can contribute to perio-
dontal disease including cigarette smoking, glucocorti-
coids and other immunosuppressants, and diseases of
immune suppression such as AIDS [36]. Included in this
list and of especial relevance to this review is vitamin D
deficiency. Using National Health and Nutrition Exami-
nation Survey (NHANES) III survey data, Dietrich et al.
[25,37] found an inverse correlation between 25(OH)D
levels and evidence of periodontal disease.
The inflammatory and immune responses initiated by
periodontal pathogens are initially part of the host
defense. The persistent activation of these processes,
however, leads to deleterious effects resulting in alveolar
bone resorption. For example, IL-8/CXCL8, a chemoat-
tractant for PMNs, is found in normal gingival tissue. In
the early stages of periodontitis, IL-8/CXCL8 levels are
increased, and PMNs are the first cells to respond [38].
Lack of or defective PMNs are associated with severe
forms of periodontal disease. With increasing severity of
the infection, however, IL-8 levels and PMN numbers
increase, leading to periodontal tissue destruction [39].

Macrophages are likely to play an important role in the
killing of pathogenic organisms, and their release of pro-
inflammatory mediators such as TNF-a, IL-1, and nitric
oxide enhances the cellular immune response. T helper
lymphocytes are also found in diseased periodontal tis-
sues. Th1 cells produce IFN-g, which activates macro-
phages; these cells are associated with more aggressive
forms of periodontitis [40]. Th2 cells produce anti-inflam-
matory cytokines such as IL-4, IL-10, and IL-13 and may
serve to dampen the inflammatory process along with
Treg lymphocytes (CD4þ, CD25þ, FoxP3þ). More
recently the Th17 lineage has emerged, the major source
of a number of members of the IL-17 family, namely
IL-17A and F [41
]. IL-17A and F can induce a number of
cytokines from various cells including IL-8/CLCL8 and
so have potent actions in recruiting PMNs. As such Th17
cells play an important role in both innate and adaptive
immune responses to infection. Finally, B lymphocytes
and plasma cells are also found in periodontal lesions, and
their numbers increase with the progression of the dis-
ease [42]. These cells may produce antibodies that assist
with the immune defense mechanism, but they may also
produce inflammatory cytokines [43] and autoantibodies
in the inflammatory environment [44] that could aggra-
vate the disease.
A number of immune processes in periodontal disease are
likely to be modulated by vitamin D, but at this point
little study of this possibility has been undertaken. With
our new understanding of the role of vitamin D in
regulation of the immune system, both adaptive and
innate, this situation is likely to change.
Conclusion
The immune system defends against bacterial infection
by activation of both adaptive and innate mechanisms,
which frequently interact. The innate immune system is
the more primitive system pre-built into cells that are on
the front line for defense against bacterial invasion,
including epithelial cells in the skin, gut, lung, and
periodontium as well as macrophages and neutrophils.
The adaptive immune system provides a more specific
response, but takes longer to develop; however, once it
has developed it provides a powerful response against
invading organisms. Vitamin D regulates both types of
immunity, suppressing adaptive immunity but poten-
tiating the innate immune response. In this brief review
I have focused on the innate immune response, and
provided three examples of where this mechanism
comes into play: the macrophage, the keratinocyte of
the epidermis, and the periodontium. At least for the
first two examples the beneficial role of vitamin D in
facilitating the ability of these cells to combat infection
is established.
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Vitamin D and the immune system Bikle 351
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Papers of particular interest, published within the annual period of review, have
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