Upregulation of Thrombomodulin Antigen Levels in U937 Cells by Combined Stimulation with Estradiol-17β and Vitamin K₂ (Menaquinone 4)

Abstract

The expression of thrombomodulin (TM) and tissue factor (TF) antigens by estradiol and vitamin K₂ were studied in human leukemic cell lines including U937 (monoblastic leukemia), NB4 (acute promyelocytic leukemia), and HL60 (acute myeloblastic leukemia). Combined stimulation with estradiol-17β and menaquinone 4 (MK4), homologue of vitamin K₂, showed a remarkable increase of total TM antigen level only in U937 cells among these leukemic cell lines, whereas a single treatment of each agent showed a modest or a moderate increase. A synergistic effect of cotreatment with estradiol-17β and MK4 was observed in an optimum concentration of 1.0 μmol of estradiol-17β and 1.0 μmol of MK4. Estrogen receptors were detected only in U937 cells among these cell lines, and the competitive assay with an antiestrogenic agent showed a suppression on TM expression in a dose-dependent manner. In the mean time, concerning expression of TF antigens, if at all, only a very slight decrease was observed by costimulation with estradiol-17β and MK4 in U937 and NB4 cells, whereas all-trans-retinoic acid (ATRA) showed a remarkable decrease in surface TF antigen levels in NB4 cells and also a modest decrease in U937 cells. These findings suggest that estradiol-17β would upregulate TM antigen expression via estrogen receptors and in cooperation with MK4, showing a different mechanism from ATRA.

Keywords:

Estradiol-17β - menaquinone 4 - thrombomodulin - tissue factor - human leukemic cells