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Synergistic factors for stem cell proliferation: further studies of the
target stem cells and the mechanism of stimulation by interleukin-1,
interleukin-6, and granulocyte colony-stimulating factor
K Ikebuchi, JN Ihle, Y Hirai, GG Wong, SC Clark and M Ogawa
Department of Medicine, Medical University of South Carolina, Charleston.
Serial observations of blast cell colony development from spleen cells of
mice treated with 5-fluorouracil (5-FU) four days earlier revealed that
either form of human interleukin-1 (IL-1 alpha or IL-1 beta) hastens the
emergence of interleukin-3 (IL-3)-dependent blast cell colonies. This
activity was essentially indistinguishable from the effect of interleukin-6
(IL-6) or granulocyte colony-stimulating factor (G-CSF) in the same system,
an effect that we have ascribed previously to a shortening of the G0 period
of the dormant stem cells. We also analyzed the time courses of colony
formation from cultures of day-2 post-5-FU marrow cells supported by IL-1
alpha, IL-6, or G-CSF alone or in combination with IL-3. In the presence of
IL-3, G-CSF and IL-6 but not IL-1 alpha hastened the development of
colonies and increased the numbers of multilineage colonies relative to
cultures of IL-3 alone. This observation, together with our previous data
from the human system, suggests that the synergistic effect of IL-1 is
likely due to induction of secondary growth factors, including IL-6 and
G-CSF, by accessory cells in culture. The effect of IL-6 on G0 was
confirmed by analysis of the cycling status of progenitor cells in
short-term culture. While neither IL-3 nor IL-6 alone had any effect on the
cycling status, the combination of factors resulted in a rapid recruitment
of quiescent cells into cell cycle (within 48 hours) as represented by a
twofold increase in the numbers of multipotential progenitors and a
significant increase in the sensitivity of these cells to 3H-thymidine with
high specific activity. Combinational testing of all of these synergistic
factors revealed that the target cell populations for the IL-1, IL-6, and
G-CSF overlap considerably, suggesting that they all may act through a
common mechanism. This is further supported by our finding that cells from
blast cell colonies grown in the presence of a combination of any one of
the synergistic factors with IL-3 replate with higher efficiency and yield
more multilineage secondary colonies than those from colonies grown in IL-3
alone. These findings provide further evidence that IL-1, IL-6, and G- CSF
serve to integrate the immediate host responses to infection through
augmentation of effector cells and antibody production as well as the
longer term host responses by recruitment of dormant hemopoietic stem cells
into active cell cycling.
Volume 72,
Issue 6,
pp. 2007-2014,
12/01/1988
Copyright © 1988 by The American Society of Hematology
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