Anticoagulant effects of 1α,25-dihydroxyvitamin D3 on human myelogenous leukemia cells and monocytes

Takatoshi Koyama, Misako Shibakura, Mai Ohsawa, Ryuichi Kamiyama, Shinsaku Hirosawa

研究成果査読

100 被引用数 (Scopus)

抄録

The hormonally active form of vitamin D is 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], which is a principal regulator of calcium homeostasis. It also affects hormone secretion, cell differentiation, and proliferation 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 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 end the VDR binds to vitamin D responsive elements on genes regulated 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.

本文言語English
ページ(範囲)160-167
ページ数8
ジャーナルBlood
92
1
DOI
出版ステータスPublished - 7月 1 1998
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 免疫学
  • 血液学
  • 細胞生物学

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