Tumor necrosis factor downregulates granulocyte-colony-stimulating factor receptor expression on human acute myeloid leukemia cells and granulocytes.
Tumor necrosis factor (TNF) inhibits granulocyte-colony-stimulating factor (G-CSF)-induced human acute myeloid leukemia (AML) growth in vitro. Incubation of blasts from three patients with AML in serum-free medium with TNF (10(3) U/ml), and subsequent binding studies using 125I-G-CSF reveal that TNF downregulates the numbers of G-CSF receptors by approximately 70%. G-CSF receptor numbers on purified blood granulocytes are also downmodulated by TNF. Downregulation of G-CSF receptor expression becomes evident within 10 min after incubation of the cells with TNF at 37 degrees C and is not associated with an apparent change of the dissociation constant (Kd). The TNF effect does not occur at 0 degrees C and cannot be induced by IL-2, IL-6, or GM-CSF. TNF probably exerts its effect through activation of protein kinase C (PKC) as the TNF effect on G-CSF receptor levels can be mimicked by 12-O-tetradecanoylphorbol-13- acetate. The PKC inhibitor Staurosporine (Sigma Chemical Co., St. Louis, MO) as well as protease inhibitors can completely prevent G-CSF receptor downmodulation. Thus, it appears TNF may act as a regulator of G-CSF receptor expression in myeloid cells and shut off G-CSF dependent hematopoiesis. The regulatory ability of TNF may explain the antagonism between TNF and G-CSF stimulation.
Elbaz
O
O
Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Budel
L M
LM
Hoogerbrugge
H
H
Touw
I P
IP
Delwel
R
R
Mahmoud
L A
LA
Löwenberg
B
B
D000208:Acute Disease; D000470:Alkaloids / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007951:Leukemia, Myeloid / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000470:Alkaloids; D011480:Protease Inhibitors; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate