title: Suppression of chronic myelogenous leukemia colony growth by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors: a novel application for inhibitors of IL-1 activity.
abstract: In this study, we investigated the role of interleukin-1 beta (IL-1 beta) in the malignant evolution of chronic myelogenous leukemia (CML) and the functional activity of IL-1 inhibitors. Bone marrow (BM) and peripheral blood (PB) low-density cells from 38 CML patients were studied in the colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte colony culture assay. Samples from patients with early stage, interferon-alpha (IFN)-sensitive disease formed hematopoietic colonies in the presence of fetal calf serum (FCS), erythropoietin (Epo), and one of the following: granulocyte-macrophage colony-stimulating factor (10 ng/mL), IL-3 (15 ng/mL), both, or phytohemagglutinin-conditioned medium. The addition of IL-1 beta augmented IFN-sensitive CML colony growth in a dose-dependent manner at concentrations of 10 to 100 U/mL. In sharp contrast, addition of the above growth factors did not augment the colony growth-promoting effect of FCS and Epo in samples from IFN-resistant patients; further, adherent cell fractionation or T-lymphocyte depletion attenuated the "autonomous" colony growth. Lysates of 2.5 x 10(7) low-density cells from each of six IFN-resistant and six IFN-sensitive CML patients and three normal volunteers were tested for intrinsic IL-1 beta content in an enzyme-linked immunosorbent assay and yielded a mean of 610 pg, 54.6 pg, and 49.4 pg of IL-1 beta, respectively (P less than .045). Interestingly, both soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) at concentrations of 5 to 100 ng/mL (sIL-1R) and 10 to 500 ng/mL (IL-1RA) inhibited CML colony growth in a dose-dependent fashion, with maximal inhibition of 64% and 65%, respectively. A similar effect was noted with the use of anti-IL-1 beta neutralizing antibodies. These data implicate IL-1 beta in CML disease progression and suggest that the inhibitory effects of molecules such as sIL-1R and IL-1RA could conceivably be the basis of a novel therapeutic strategy against this disorder.
authors.affiliation: Department of Clinical Immunology and Biological Therapy, University of Texas M.D. Anderson Cancer Center, Houston 77030.
authors.forename: Z
authors.initials: Z
authors.lastname: Estrov
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
authors.forename: M
authors.initials: M
authors.lastname: Wetzler
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: M
authors.initials: M
authors.lastname: Blake
authors.forename: D
authors.initials: D
authors.lastname: Harris
authors.forename: J U
authors.initials: JU
authors.lastname: Gutterman
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004351:Drug Resistance; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000494:pharmacology*; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D014410:Tumor Stem Cell Assay
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011506:Proteins; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007372:Interferons