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Interleukin-1 stimulates proliferation of acute myeloblastic leukemia cells
by induction of granulocyte-macrophage colony-stimulating factor release
R Delwel, C van Buitenen, M Salem, F Bot, S Gillis, K Kaushansky, B Altrock and B Lowenberg
Dr Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
In this study, we further established the role of interleukin-1 (IL-1)
alpha and IL-1 beta as regulators of proliferation of acute myeloid
leukemia (AML) cells. IL-1 stimulated tritiated thymidine (3H-TdR) uptake
of AML cells in 13 of 28 cases. Cytogenetic analysis confirmed the leukemic
clonality of the IL-1-stimulated cells. Most likely, IL-1 exerted these
stimulative effects directly on AML blast cells because IL-1 effectively
induced 3H-TdR uptake of CD34-positive AML blasts (separated following cell
sorting). Furthermore, adherent cell-depleted AML samples of three patients
were more effectively stimulated than nondepleted AML fractions. Cluster
and colony formation from adherent cell depleted AML samples could also be
stimulated with IL-1, ie, in seven of ten cases analyzed. Subsequent
experiments indicated that IL-1 stimulation depended on the release of
GM-CSF because (1) induction of DNA synthesis of AML cells by IL-1 could be
abrogated with antigranulocyte-macrophage colony-stimulating factor
(GM-CSF) antibody, (2) conditioned media (CM) prepared from IL-1 stimulated
AML blasts (adherent cell depleted) could stimulate the proliferation of
purified normal bone marrow progenitors whereas supernatants from
nonstimulated AML blasts did not, and (3) GM-CSF was demonstrated in
IL-1/AML-CM with a specific radioimmunoassay, while GM-CSF was not
detectable in nonstimulated supernatants. In one case of AML showing
significant 3H- TdR uptake in the absence of CSFs, this spontaneous DNA
synthesis was found to depend on autocrine IL-1 beta release as it could be
suppressed with anti-IL-1 beta antibody or anti-GM-CSF. The blockade by
anti-IL-1 beta could be overcome by the addition of high concentrations of
IL-1 beta as well as GM-CSF. Thus, in this particular case, endogenously
produced IL-1 beta had stimulated the release of GM-CSF which resulted in
GM-CSF-dependent proliferation. The results indicate that GM-CSF production
by AML blasts is often regulated by IL-1 rather than being constitutive.
Volume 74,
Issue 2,
pp. 586-593,
08/01/1989
Copyright © 1989 by The American Society of Hematology
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