Page 267 - Vitamin D and Cancer

254 R. Okamoto et al.

higher levels of VDR than tissue macrophages [10]. VDR protein levels of
peripheral blood monocytes have been reported to be two-fold higher in patients
with idiopathic hypercalciuria with normal serum 1,25(OH) D levels compared to
2 3
monocytes from normal individuals [11]. On the other hand, fewer receptors have
been detected in the peripheral blood mononuclear cells of patients with X-linked
hypophosphatemic rickets [12]. These individuals have a significant positive
correlation between VDR concentration in their mononuclear cells and their serum
phosphate levels (p < 0.05).
Examination of a large number of myeloid leukemia cell lines blocked at various
stages of maturation showed that they all expressed VDR, albeit at different levels
–7
[5]. Treatment of HL-60 myeloblastic leukemia cells with 1,25(OH) D (10 M)
2 3
decreases their VDR protein levels by 50% at 24 h and levels return to normal after
72 h. No change of VDR mRNA expression occurred in the cells [5, 13], suggesting
that one of the major sites of regulation of expression of VDR occurs at the post
transcriptional level. Exposure to 1,25(OH) D induces the VDR to move from the
2 3
cytoplasm to the nucleus, and this translocation is prevented by treatment with
inhibitors of the PI3-K (LY294002) and the MAPK (PD98059) pathways [14].
Their monocyte-like differentiation of HL-60 cells treated with 1,25(OH) D may
2 3
require functional activator protein-l (AP-1) complexes which bind to the TRE of
the promoter region in human VDR [15] (Sect. 11.4.2.1).

11.2.2 Vitamin D Receptors in Lymphoid Cells

Subsets of thymocytes, resting T lymphocytes especially those expressing either
CD8+ or CD4+ and activated T lymphocytes express VDR [5, 16, 17]. VDR
mRNA expression increases when these cells are stimulated to proliferate, for
example after their exposure to phytohemagglutinin-A (PHA) for 24 h in vitro.
Another major site of regulation of VDR expression in these cells is at the tran-
scriptional level [5, 16]. No VDR mRNA or protein was detected in resting B
lymphocytes, but VDR was up-regulated via cellular activation in vitro and in vivo,
for example in normal human B cells from tonsils [16, 18]. 1,25(OH) D inhibits
2 3
the synthesis of immunoglobulins (Ig) synthesized by B lymphocytes in vitro [19].
Their inhibition may be mediated through activation of VDR/RXR in these cells,
and/or through the inhibition of T-helper activity [20]. Production of lymphokines,
including IL-2, is markedly decreased by 1,25(OH) D in activated T lymphocytes,
2 3
and this could cause the suppression of Ig synthesis [21–24]. The effects of vita-
min D on the immune system are discussed in Chapter 6.
Levels of VDR mRNA in leukocytes from healthy individuals after an oral
administration of 1,25(OH) D increased an average of 1.2 to 11.1-fold [25]. The
2 3
maximum increase of VDR mRNA levels occur over 1 and 5 h, with a mean of
3.6 h. Expression of VDR is induced in the lymphocytes of patients with rheuma-
toid arthritis and in pulmonary lymphocytes of patients with tuberculosis and
sarcoidosis [26–28]. Moreover, low levels of VDR expression were detected in