Inhibition of acute myelogenous leukemia blast proliferation by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors.
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.
Department of Clinical Immunology and Biological Therapy, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Z
Z
Estrov
R
R
Kurzrock
E
E
Estey
M
M
Wetzler
A
A
Ferrajoli
D
D
Harris
M
M
Blake
J U
JU
Gutterman
M
M
Talpaz
D000328:Adult; D000368:Aged; D001752:Blast Crisis / Q000473:pathology*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology*; D002455:Cell Division; D002478:Cells, Cultured; D003470:Culture Media; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins; D019089:Stem Cell Factor; D013601:T-Lymphocytes / Q000276:immunology; D014410:Tumor Stem Cell Assay
D003470:Culture Media; D016298:Hematopoietic Cell Growth Factors; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D011506:Proteins; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor