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.

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Abstract
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 G1. The inhibitory effect on IL-3-dependent growth of IC2 cells was not increased when these cells were exposed simultaneously to TFG-.beta. and IAP. These 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 G1 period. It is also suggested that IAP and TGF-.beta. retard the growth of IC2 cells by increasing the fraction of cells in G1.

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