M-CSF-mediated macrophage differentiation but not proliferation is correlated with increased and prolonged ERK activation.
M-CSF is a cytokine essential for both the proliferation and differentiation of monocytes/macrophages. In this study, we established a new M-CSF-mediated differentiation-inducing system, and examined how the level and duration of the activation of ERK preceded M-CSF-mediated differentiation. TF-1-fms human leukemia cells rapidly proliferated in response to M-CSF. However, in the presence of a phorbol ester, TPA, TF-1-fms cells definitely switched their responsiveness to M-CSF from proliferation to differentiation, as evidenced by a more drastic morphological change and the appearance of cells with a higher level of phagocytic activity. In TF-1-fms cells expressing HIV-1 Nef protein in a conditionally active-manner, both M-CSF-mediated proliferation and M-CSF/TPA-mediated differentiation were inhibited by the activation of Nef. The Nef-active cells showed perturbed patterns of ERK activation. Under the proliferation-inducing conditions (TPA-free), parental or Nef-inactive cells showed modest ERK activation following M-CSF stimulation, whereas Nef-active cells showed an earlier and transient ERK activation, despite a decrease in their proliferation rate. Under the differentiation-inducing conditions, parental or Nef-inactive cells showed increased and prolonged ERK activation following M-CSF stimulation, whereas Nef-active cells showed transient ERK activation. These results supported the idea that the increased and prolonged ERK activation led to M-CSF-mediated macrophage differentiation but not to proliferation.
Suzu
Shinya
S
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
Hiyoshi
Masateru
M
Yoshidomi
Yuka
Y
Harada
Hideki
H
Takeya
Motohiro
M
Kimura
Fumihiko
F
Motoyoshi
Kazuo
K
Okada
Seiji
S
D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D054311:nef Gene Products, Human Immunodeficiency Virus; D016173:Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate