Growth regulation of multi-factor-dependent myeloid cell lines: IL-4, TGF-beta and pertussis toxin modulate IL-3- or GM-CSF-induced growth by controlling cell cycle length.
The stimulatory effects of lymphokines, interleukin 3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (IL-4), and the inhibitory effects of transforming growth factor beta (TGF-beta) and the pertussis toxin, islet activating protein (LAP), on multi-factor-dependent myeloid cell lines were examined. The effects of IL-3 on a mast cell progenitor clone, IC2 were indistinguishable from those of GM-CSF with respect to their concentration-response curves for induction of DNA synthesis and capability to maintain cell growth for many months. IL-4 acts differently on IC2 cells: the maximum level of DNA synthesis induced by IL-4 is always lower than that induced by IL-3 or GM-CSF and IL-4-induced proliferation is transient. IL-4, however, synergistically induced DNA synthesis of IC2 cells with limiting concentrations of IL-3 or GM-CSF. When IC2 cells were cultured with saturating concentrations of IL-3, GM-CSF or a combination of both, the doubling time was 25 +/- 1 h, whereas it decreased to 17 +/- 1 h when IL-4 was further added to the cultures. IAP reduced the DNA synthesis of IC2 cells induced by the above three growth factors. The doubling time of IC2 cells was 30 +/- 2 h when IC2 cells were cultured with sufficient concentrations of IL-3 in the presence of IAP. Cell cycle analysis revealed that the fraction of cells in Gl was decreased by IL-4 but was increased by IAP. TGF-beta also reduced IL-3-dependent DNA synthesis and increased the fraction of cells in Gl. The inhibitory effect on IL-3-dependent growth of IC2 cells was not increased when these cells were exposed simultaneously to TGF-beta and IAP. The results suggest that IL-3 and GM-CSF stimulate the growth of IC2 cells through similar pathways and that IL-4 augments the action of IL-3 or GM-CSF by decreasing the Gl period. It is also suggested that IAP and TGF-beta retard the growth of IC2 cells by increasing the fraction of cells in GI.
Koyasu
S
S
Department of Cell Biology, Tokyo Metropolitan Institute of Medical Science.
Miyajima
A
A
Arai
K
K
Okajima
F
F
Ui
M
M
Yahara
I
I
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology* / Q000502:physiology; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D037342:Pertussis Toxin; D015291:Transforming Growth Factors / Q000494:pharmacology* / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology* / Q000502:physiology
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007377:Interleukin-3; D010566:Virulence Factors, Bordetella; D015847:Interleukin-4; D015291:Transforming Growth Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; D037342:Pertussis Toxin