Page 268 - Vitamin D and Cancer

11 Vitamin D and Hematologic Malignancies 255

low-grade, non-Hodgkin’s lymphoma (NHL) and in the follicular lymphoma B-cell
lines SU-DHL4 and SU-DHL5 [29].

11.2.3 Hematopoiesis in VDR Knockout Mice

Studies by us using VDR knockout (KO) mice indicated that expression of VDR is
dispensable for normal hematopoiesis [30]. No difference in the numbers and
percentages of red and white blood cells were found between VDR KO and wild-type
(WT) mice. Committed myeloid stem cells from the bone marrow cultured in meth-
ylcellulose formed similar numbers of colonies when grown in the presence of vari-
ous cytokines including GM-CSF, G-CSF, M-CSF either alone or in combination
with IL-3. Furthermore, bone marrow progenitor cells from VDR KO and WT mice
formed a similar number and percentage of granulocyte, macrophage and granulo-
cyte/macrophage mixed colonies when cultured in methylcellulose with GM-CSF
and IL-3. Under these conditions, treatment with 1,25(OH) D dramatically
2 3
increased the percentage of macrophage colonies derived from WT but not VDR
KO bone marrow cultures. This observation demonstrates the requirement of VDR
expression for 1,25(OH) D -induction of bone marrow progenitors into monocytes/
2 3
macrophages. The proportions of T- and B-cells were normal in the VDR KO mice.
However, the antigen-stimulated spleen cells from VDR KO mice produced less
IFNg and more IL-4 than those from WT mice, indicating impaired Th1 differentia-
tion. Additionally, IL-12 stimulation induced a weaker proliferative response in
VDR KO splenocytes as compared to those in WT mice, and expression of STAT4
was reduced. These results suggest that VDR plays an important role in the Thl-
type immune response but not T cell development. Interestingly, another report
using VDR KO mice showed that VDR is required for normal development and
function of Val4 invariant natural killer T (iNKT) cells which are involved in
immune regulation, host defense against pathogens and tumor surveillance [31].

11.3 Effects of Vitamin D Compounds on Normal
Hematopoiesis

1,25(OH) D modulates the differentiation of normal hematopoietic progenitors.
2 3
Normal human bone marrow committed stem cells cultured in either soft agar or
liquid culture with 1,25(OH) D differentiate into macrophages. Likewise, mono-
2 3
cytes cultured in serum-free medium with 1,25(OH) D become macrophages
2 3
within 7 days [32–37]. These macrophages are functionally competent [35].
–10
Concentrations of 1,25(OH) D causing this differentiation ranges between 10 M
2 3
–7
(slightly higher than physiological serum level) to 10 M. On the other hand,
1,25(OH) D (10 to 10 M) can inhibit the differentiation into CDla + dendritic
–9
–7
2 3
cells [38].