Effect of ATRA and ATO on the expression of tissue factor in NB4 acute promyelocytic leukemia cells and regulatory function of the inflammatory cytokines TNF and IL-1β.
The characteristic hemorrhages of acute promyelocytic leukemia (APL) are caused in part by the high expression of tissue factor (TF) on leukemic cells, which also produce TNF and IL-1β, proinflammatory cytokines known to increase TF in various cell types. Exposure of NB4 cells, an APL cell line, to all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) rapidly and strongly reduced TF mRNA. Both drugs also reduced TNF mRNA, but later, and moreover increased IL-1β mRNA. The effect on procoagulant activity of cells and microparticles, as measured with calibrated automated thrombography, was delayed and only partial at 24 h. TNF and IL-1β inhibition reduced TF mRNA and activity only partially. Inhibition of the inflammatory signaling intermediate p38 reduced TF mRNA by one third but increased TNF and IL-1β mRNA. NF-κB inhibition reduced, within 1 h, TF and TNF mRNA but did not change IL-1β mRNA, and rapidly and markedly reduced cell survival, with procoagulant properties still being present. In conclusion, although we provide evidence that TNF, IL-1β, and their signaling intermediates have a regulatory function on TF expression by NB4 APL cells, the effect of ATRA and ATO on TF can only partially be accounted for by their impact on these cytokines.
Division of Angiology and Hemostasis, Department of Medical Specialties, University Hospital of Geneva, Geneva, Switzerland.|Faculty of Medicine of the University of Geneva, Geneva, Switzerland.
Sylvie
S
Dunoyer-Geindre
Division of Angiology and Hemostasis, Department of Medical Specialties, University Hospital of Geneva, Geneva, Switzerland.|Faculty of Medicine of the University of Geneva, Geneva, Switzerland.
Anne-Sophie
AS
Rivier-Cordey
Division of Hematology, Department of Medical Specialties, University Hospital of Geneva, Rue Gabrielle Perret-Gentil 4, 1211, Geneva, Switzerland.
Olga
O
Tsopra
Division of Hematology, Department of Medical Specialties, University Hospital of Geneva, Rue Gabrielle Perret-Gentil 4, 1211, Geneva, Switzerland. ThomasPierre.Lecompte@hcuge.ch.
Thomas
T
Lecompte
Division of Angiology and Hemostasis, Department of Medical Specialties, University Hospital of Geneva, Geneva, Switzerland.|Faculty of Medicine of the University of Geneva, Geneva, Switzerland.
Egbert K O
EKO
Kruithof
D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013925:Thromboplastin / Q000235:genetics*; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D039521:CD11c Antigen; D004791:Enzyme Inhibitors; D007093:Imidazoles; D053583:Interleukin-1beta; D016328:NF-kappa B; D010087:Oxides; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014212:Tretinoin; D013925:Thromboplastin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D000077237:Arsenic Trioxide
Acute promyelocytic leukemia; All-trans retinoic acid; Arsenic trioxide; Interleukin 1 beta; Tissue factor; Tumor necrosis factor