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Anticoagulant Effects of 1 ,25-Dihydroxyvitamin D3 on
Human Myelogenous Leukemia Cells and Monocytes
Takatoshi Koyama,
Misako Shibakura,
Mai Ohsawa,
Ryuichi Kamiyama, and
Shinsaku Hirosawa
From the School of Allied Health Sciences and the First Department of
Internal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
The hormonally active form of vitamin D is 1 ,25-dihydroxyvitamin
D3 [1,25(OH)2D3], which is a
principal regulator of calcium homeostasis. It also
affects hormone secretion, cell differentiation, and proliferation by a
mode of action that involves stereospecific interaction with an
intracellular vitamin D receptor (VDR). We recently found that
retinoids, which are vitamin A derivatives, exert anticoagulant effects
by upregulating thrombomodulin (TM) and downregulating tissue factor
(TF) expression in acute promyelocytic leukemia cells and monoblastic
leukemia cells. Both the VDR and retinoid receptors belong to the same
family of receptors. A heterodimer consisting of the retinoid X
receptor and the VDR binds to vitamin D responsive elements on genes
regulated by vitamin D. To determine whether
1,25(OH)2D3 would exhibit anticoagulant effects
similar to retinoids, we measured the antigen level, activity, and mRNA level of TM and TF in human leukemic cells, vascular endothelial cells,
and monocytes treated with 1,25(OH)2D3. We
found that 1,25(OH)2D3 upregulates antigen
expression, activity, and mRNA levels of TM and downregulates antigen
expression, activity, and mRNA levels of TF in human monocytic leukemia
cells, some acute myelogenous leukemia cells, and monocytes, but not in
umbilical vein endothelial cells. Transient transfection studies with
reporter plasmids in monocytic leukemia cells and mobility gel-shift
assay showed interaction with 1,25(OH)2D3 and
functional retinoic acid responsive elements present in the
5 -flanking region of the TM gene. However, auxiliary factors or
other elements in the TM gene may contribute to VDR specificity and
transactivation of the gene in specific target cells. These findings
indicate that 1,25(OH)2D3 resembles the retinoids in its control of the transcription of the TM and TF genes in
human monocytic cells. Analogs of 1,25(OH)2D3
with anticoagulant activity may serve as adjunctive antithrombotic
agents in monocytic leukemia and atherosclerotic disease.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 160-167
© 1998 by The American Society of Hematology.
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