Immunoregulatory properties

Background information can be found in Chapter 5.
8.7.1 Presence of the vitamin D receptor in
cells of the immune system
The VDR has been identifi ed in almost all nucleated
cell types in the body, including malignant and
non-malignant cells of haemopoietic origin. Peripheral
blood monocytes express the VDR constitutively.
Resting T and B lymphocytes do not express the VDR:
only when activated by mitogens and antigens do
these cells express the receptor. Interaction of T-cell
receptors with the peptide–MHC complex of antigenpresenting
tissue cells and cells of the immune system
leads to T-cell activation and subsequent gene expression
events (Manolagas et al., 1990).
Vitamin D 219
8.7.2 In vitro effects of 1α,25-dihydroxyvitamin
D3 on cells of the immune system
Monocytes/macrophages
1α,25-Dihydroxyvitamin D3 inhibits proliferation
and promotes differentiation of bone marrow-derived
macrophage precursors and specifi cally promotes expression
of the differentiation-associated cell membrane
receptor (mannose receptor) (Clohisy et al.,
1987). The relatively quiescent resident macrophages
are activated by immunogenic stimuli to become
activated macrophages, now with a greatly enhanced
ability to phagocytose and destroy pathogens.
1α,25-Dihydroxyvitamin D3 appears to be essential
for macrophage activation. Gavison & Bar-Shavit
(1989) reported that macrophages from vitamin
D-defi cient mice injected with activating or eliciting
agents had defective anti-tumour activity and
an impaired respiratory burst (low production of
hydrogen peroxide and superoxide). Activity of the
lysosomal enzyme acid phosphatase was unaffected
by vitamin D defi ciency. Incubation of the vitamin
D-defi cient macrophages with 1α,25(OH)2D3 markedly
enhanced their anti-tumour activity, but did not
affect the cells’ capacity to produce hydrogen peroxide
and superoxide, or acid phosphatase. Abe et al. (1984)
reported that 1α,25(OH)2D3 increases the number
of Fc receptors on the surface of macrophages and
induces cytotoxicity.
In cultured monocytes, 1α,25(OH)2D3 enhances
by two- to three-fold the IFN-γ-induced expression
of major histocompatibility complex (MHC) class
II molecules that mediate antigen presentation to T
lymphocytes (Morel et al., 1986). Pre-treatment of
normal human monocytes with 1,25(OH)2D3 enhances
their responsiveness to various chemoattractants
(Girasole et al., 1990). Augmented monocyte
chemotaxis to FMLP is associated with an increased
number of high-affi nity binding sites for this chemoattractant.
The hormone is also able to stimulate
the migratory capacity of monocytes obtained from
patients with acquired immune defi ciency syndrome
(AIDS), a condition associated with impaired monocyte
chemotaxis. 1α,25(OH)2D3 increased production
of IL-1 by human peripheral blood monocytes
(Bhalla et al., 1986) and also enhanced these cells’
capacity for lipopolysaccharide-triggered release of
tumour necrosis factor (Rook et al., 1987). Incubation
of monocytes with 1α,25(OH)2D3 at 45°C led
to an increased synthesis of heat shock proteins accompanied
by a relative preservation of total protein
synthesis (Polla et al., 1986).
It has been postulated that vitamin D may have
a protective role in tuberculosis infection (Davies,
1985). The bacterium responsible for tuberculosis is
a bacillus, Mycobacterium tuberculosis. Monocytes,
although phagocytic, have only a limited capacity
to kill M. tuberculosis and can become infected with
the bacillus in vitro. However, any bacilli released by
dying monocytes are rapidly phagocytosed by other
cells, especially macrophages, and destroyed. Rook et
al. (1986) reported that 1α,25(OH)2D3 inhibited the
growth of M. tuberculosis in cultured human monocytes
and IFN-γ enhanced this inhibition. They also
showed that incubation of monocytes with IFN-γ
led to increased ability to metabolize 25(OH)D3 to
1α,25(OH)2D3. This ability has also been demonstrated
in normal human macrophages (Koeffl er et
al., 1985). Based on these observations, a possible
scenario is that infected monocytes produce IFN-γ
which induces these cells to synthesize 1α,25(OH)2D3
from circulating 25(OH)D3. The locally produced
hormone stimulates monocytes to differentiate into
macrophages, which are better equipped to deal with
the infection.
Natural killer cells
Merino et al. (1989) showed that 1,25(OH)2D3 inhibits
the generation of cytotoxic activity from cultured
natural killer cells. The hormone was, however, unable
to interfere with the cytotoxic function of cells already
established, placing the inhibition at the level of natural
killer cell activation.
Lymphocytes
In contrast to the stimulatory effects of 1α,25(OH)2D3
on the innate arm of the immune response, the principal
action of the hormone on the acquired immune
response, mediated by lymphocytes, is immunosuppression.
1α,25(OH)2D3 inhibits T-lymphocyte
proliferation after these cells have been activated and
the VDR is expressed. The hormone prevents entry
of the cells into the S phase of the cell cycle by blocking
the RNA synthesis required for the transition of
cells from early G1 to late G1 (Rigby et al., 1985).
1α,25-Dihydroxyvitamin D3 also inhibits the growthpromoting
interleukin-2 (IL-2) (Tsoukas et al., 1984).
Inhibitors of IL-2 synthesis block the cell cycle at the
220 Vitamins: their role in the human body
same point as 1α,25(OH)2D3 blocks the cycle, suggesting
that the inhibitory effect of 1α,25(OH)2D3
on T-cell proliferation is mediated by IL-2. Alroy et
al. (1995) demonstrated that 1α,25(OH)2D3 represses
IL-2 gene transcription by a direct, VDR-dependent
effect. In the absence of intracellular 1α,25(OH)2D3,
the IL-2 gene in T lymphocytes is activated by the
binding of a T-cell-specifi c transcription factor,
NFATp, to an NF-AT-1 element and subsequent
recruitment of the ubiquitous transcription factors
Jun and Fos (AP-1). VDR–RXR heterodimers, which
would form in response to the intracellular presence
of 1α,25(OH)2D3, directly inhibit the interaction
between AP-1 and NFATp. Moreover, the stable binding
of VDR–RXR to the NF-AT-1 element blocks the
binding of any NFATp–AP-1 that may subsequently
be formed; however, prebound NFATp–AP-1 cannot
be destabilized by VDR–RXR. The suppressive effect
of 1α,25(OH)2D3 on lymphocyte proliferation
is countered indirectly by IL-1 produced by monocytes
in response to stimulation by 1α,25(OH)2D3
(Bhalla et al., 1986). IL-1 potentiates the release of
IL-2 from activated T cells and the IL-2 stimulates
lymphocyte proliferation. These differential effects of
1α,25(OH)2D3 provide a fi nely tuned mechanism for
regulating T-cell proliferation.
Lemire et al. (1984) demonstrated an inhibitory
role of 1α,25(OH)2D3 on proliferation and immunoglobulin
production by normal activated human
peripheral blood mononuclear cells in vitro. Further
studies revealed the T helper cell to be particularly
suppressed by 1α,25(OH)2D3 (Lemire et al., 1985). T
helper cells are divided into Th1 and Th2 subsets on
the basis of their pattern of cytokine secretion. Th1
cells secrete interleukin (IL-2) and interferon (IFN-γ)
and induce B cells to produce immunoglobulin IgG2a,
while Th2 cells secrete IL-4 and IL-10 and induce the
production of IgG1 and IgE by B cells. IL-12 that is
produced by macrophages and B cells induces IFN-
γ secretion by natural killer cells and Th1 cells and
promotes the differentiation of Th1 cells from their
uncommitted precursors.
Pre-incubation of T helper cells with 1α,25(OH)2D3
prevents these cells from inducing B cells to synthesize
immunoglobulin. The hormone also reduces mRNA
levels for IL-2 and IFN-γ in T helper cells. These observations
are consistent with a selective suppressive
effect of 1α,25(OH)2D3 on Th1 cells. 1α,25(OH)2D3
also inhibits the secretion of IL-12 by macrophages
and B cells, thereby preventing the differentiation of
precursor cells to Th1 cells (Lemire et al., 1995). Thus,
the immunosuppressive activity of 1α,25(OH)2D3
that takes place in vitro is aimed specifi cally at Th1
cells, preventing their expression both directly or
indirectly through inhibition of macrophage-derived
IL-12.
Meehan et al. (1992) studied the effects of
1α,25(OH)2D3 on the human mixed lymphocyte
reaction (MLR), the in vitro model of transplant
compatibility. The hormone stimulated suppressor
T-cell activity and prevented the generation of
cytotoxic T-cell activity. A signifi cant reduction in
expression of MHC class II molecules (but not class
I molecules) was also observed in the presence of the
hormone. The suppression of IFN-γ production by
1α,25(OH)2D3 could explain the latter effect. The effects
of 1α,25(OH)2D3 on the MLR are similar to those
of the potent immunosuppressive drug, cyclosporin A
(Hess & Tutschka, 1980).