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Inhibition of acute myelogenous leukemia blast proliferation by
interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors
Z Estrov, R Kurzrock, E Estey, M Wetzler, A Ferrajoli, D Harris, M Blake, JU Gutterman and M Talpaz
Department of Clinical Immunology and Biological Therapy, University of
Texas M.D. Anderson Cancer Center, Houston 77030.
Interleukin-1 (IL-1) has recently been reported to play an important role
in acute myelogenous leukemia (AML) blast proliferation. We therefore
investigated the effect of soluble IL-1 receptors (sIL-1R) and IL-1
receptor antagonist (IL-1RA) on the growth of AML bone marrow blast
progenitors from 25 patients. In the AML blast colony culture assay, sIL-1R
and IL-1RA inhibited blast colony-forming cell replication in a
dose-dependent fashion, at concentrations ranging from 10 to 500 ng/mL
(sIL-1R) and 10 to 1,000 ng/mL (IL-1RA), and their inhibitory effect was
partially reversed by IL-1 beta. A similar inhibitory effect was also noted
with the use of anti-IL-1 beta neutralizing antibodies. When AML blast
progenitors were grown either in the presence of fetal calf serum (FCS)
alone or with one of the following: phytohemagglutinin
leukocyte-conditioned medium (PHA-LCM), granulocyte-macrophage
colony-stimulating factor (GM-CSF), G-CSF, interleukin-3 (IL-3), or stem
cell factor (SCF), addition of 100 ng/mL sIL-1R or IL-1RA inhibited blast
colony formation by 3% to 96% and 2% to 97%, respectively. In sharp
contrast, neither of these IL-1- inhibitory molecules significantly
inhibited proliferation of normal marrow hematopoietic progenitors. Lysates
of 2 x 10(7) low-density AML marrow cells were tested for intrinsic IL-1
beta content using an enzyme-linked immunoadsorbant assay (ELISA). Samples
from five of six patients showed high concentrations (ranging from 501 to
2,041 pg), whereas 2 x 10(7) cells from two normal marrow aspirates yielded
54.6 pg of IL-1 beta. AML blast colony-forming cells from all six patients
were inhibited by sIL-1R, IL-1RA, or both. Incubation of nine samples of
AML low-density cells with either sIL-1R or IL-1RA reduced GM-CSF
concentrations in cell lysates, and supernatants from nine (P less than
.01) and six samples (P less than .037), respectively, and G-CSF
concentration in lysates from six of nine samples (P less than .03), and in
supernatants from five of six samples (P less than .06) when studied by
ELISAs. Our data implicate IL-1 in AML blast proliferation and suggest the
potential benefits of using IL-1-inhibitory molecules in future therapies
for AML.
Volume 79,
Issue 8,
pp. 1938-1945,
04/15/1992
Copyright © 1992 by The American Society of Hematology
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