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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1995 Feb;86(2):208–216. doi: 10.1111/j.1349-7006.1995.tb03041.x

Preferential Production of Interleukin‐1β over Interleukin‐1 Receptor Antagonist Contributes to Proliferation and Suppression of Apoptosis in Leukemic Cells

Yusuke Furukawa 1, Jiro Kikuchi 1,3, Yasuhito Terui 1, Seiichi Kitagawa 1, Masatsugu Ohta 1, Yasusada Miura 2, Masaki Saito 1,✉
PMCID: PMC5920749  PMID: 7730146

Abstract

Normal human monocytes were isolated in a nascent state by centrifugal elutriation and used for the study of interleukin‐1 (IL‐1) and interleukin‐1 receptor antagonist (IL‐1ra) expression. Neither IL‐1β nor IL‐1ra mRNA was present in monocytes just after the isolation, but they were induced simultaneously in response to various stimulants. In contrast, only IL‐1β mRNA was expressed in monocytic leukemia cell line JOSK‐1, while little or no IL‐1ra mRNA was detected even after stimulation. Dominant expression of IL‐1β over IL‐1ra was also observed in fresh leukemia cells including monocytic leukemias, i.e., IL‐1βmRNA was constitutively expressed in 26 out of 36 cases (72.2%), whereas IL‐1ra mRNA was present only in 8 cases (22.2%). The signal intensity of IL‐1βmRNA was stronger than that of IL‐1ra even in IL‐1ra‐positive cases. Apoptotic cell death of monocytes was significantly inhibited by IL‐1β, and it was enhanced by IL‐1ra. In fresh leukemia cells, 3H‐thymidine uptake was generally higher in IL‐1‐producing cases than in IL‐1ra‐producing cases, and was increased by the addition of IL‐1β in all cases tested. Cell proliferation was inhibited by either IL‐1ra or anti‐IL‐1β antibody in IL‐1‐producing cases, while it was enhanced by anti‐IL‐1ra antibody in IL‐1ra‐producing cases. These results suggest that the balance between IL‐1 and IL‐1ra is necessary for homeostasis of the mononuclear phagocytosis system. The imbalance between these two counter‐acting cytokines might contribute to the altered growth and accumulation of leukemic cells.

Keywords: Interleukin‐1β, Interleukin‐1 receptor antagonist, Monocyte, Leukemia, Apoptosis

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REFERENCES

  • 1).Cannistra , S. A. and Griffin , J. D.Regulation of the production and function of granulocytes and monocytes . Sem. Hematol. , 25 , 17 – 188 ( 1988. ). [PubMed] [Google Scholar]
  • 2).Ziegler‐Heitbrock , H.‐W. L.The biology of the monocyte system . Eur. J. Cell Biol. , 49 , 1 – 12 ( 1989. ). [PubMed] [Google Scholar]
  • 3).Nathan , C. F.Secretory products of macrophages . J. Clin. Invest. , 79 , 319 – 326 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4).Dinarello , C. A.Interleukin‐1 and interleukin‐1 antagonism . Blood , 77 , 1627 – 1652 ( 1991. ). [PubMed] [Google Scholar]
  • 5).Hannum , C. H. , Wilcox , C. J. , Arend , W. P. , Joslin , F. G.Dripps , D. J. , Heimdal , P. L. , Armes , L. G. , Sommer , A. , Eisenberg , S. P. and Thompson , R. C.Interleukin‐1 receptor antagonist activity of a human interleukin‐1 inhibitor . Nature , 343 , 336 – 340 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 6).Eisenberg , S. P. , Evans , R. J. , Arend , W. P. , Verderber , E. , Brewer , M. T. , Hannum , C. H. and Thompson , R. C.Primary structure and functional expression from complementary DNA of a human interleukin‐1 receptor antagonist . Nature , 343 , 341 – 346 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 7).Carter , D. B. , Deibel , M. R. J. , Dunn , C. J. , Tomich , C. S. , Laborde , A. L. , Slighton , J. L. , Berger , A. E. , Bienkowski , M. J. , Sun , F. F. , McEwan , R. N. , Harris , P. K. W. , Yem , A. W. , Waszak , G. A. , Chosay , J. G. , Sieu , L. C. , Hardee , M. M. , Zucher‐Neeley , H. A. , Reardon , I. M. , Heinrickson , R. L. , Truesdall , S. E. , Shelly , J. A. , Eessalu , T. E. , Taylor , B. M. and Tracey , D. E.Purification, cloning, expression and biological characterization of an interleukin‐1 receptor antagonist protein . Nature , 344 , 633 – 638 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 8).Dinarello , C. A. and Wolff , S. M.The role of interleukin‐1 in disease . N. Engl. J. Med. , 328 , 106 – 113 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 9).Ohlsson , K. , Bjork , P. , Bergenfeldt , M. , Hageman , R. and Thompson , R. C.Interleukin‐1 receptor antagonist reduces mortality from endotoxin shock . Nature , 348 , 550 – 552 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 10).Granowitz , E. V. , Porat , R. , Mier , J. W. , Orencole , S. F. , Callahan , M. V. , Cannon , J. G. , Lynch , E. A. , Ye , K. , Poutsiaka , D. D. , Vannier , E. , Shapiro , J. P. , Stiles , D. M. , Catalano , M. A. , Wolff , S. M. and Dinarello , C. A.Hematologic and immunomodulatory effects of an interleukin‐1 receptor antagonist coinfusion during low‐dose endotoxemia in healthy humans . Blood , 82 , 2985 – 2990 ( 1993. ). [PubMed] [Google Scholar]
  • 11).Granowitz , E. V. , Santos , A. A. , Poutsiaka , D. D. , Cannon , J. G. , Wilmore , D. W. , Wolff , S. M. and Dinarello , C. A.Production of interleukin‐1‐receptor antagonist during experimental endotoxaemia . Lancet , 338 , 1423 – 1424 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 12).Cominelli , F. , Bortolami , M. , Pizarro , T. T. , Monsacchi , L. , Ferretti , M. , Brewer , M. T. , Eisenberg , S. P. and Ng , R. K.Rabbit interleukin‐1 receptor antagonist . J. Biol. Chem. , 269 , 6962 – 6971 ( 1994. ). [PubMed] [Google Scholar]
  • 13).Arend , W. P. and Dayer , J.‐M.Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis . Arthritis Rheum. , 33 , 305 – 315 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 14).Miller , L. C. , Lynch , E. A. , Isa , S. , Logan , J. W. , Dinarello , C. A. and Steere , A. C.The balance of synovial fluid IL‐1 and IL‐1 receptor antagonist and recovery from Lyme arthritis . Lancet , 341 , 146 – 148 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 15).Guss , H. J. , Dolken , G. , Brach , M. A. , Mertelsmann , R. and Herrmann , F.High concentrations of the interleukin‐1 receptor antagonist in serum of patients with Hodgkin's disease . Lancet , 340 , 968 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 16).Hammerberg , C. , Arend , W. P. , Fisher , G. J. , Chan , L. S. , Berger , A. E. , Haskill , J. S. , Voorhees , J. J. and Cooper , K. D.Interleukin‐1 receptor antagonist in normal and psoriatic epidermis . J. Clin. Invest. , 90 , 571 – 583 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17).Yuo , A. , Kitagawa , S. , Motoyoshi , K. , Azuma , E. , Saito , M. and Takaku , F.Rapid priming of human monocytes by human hematopoietic growth factors: granulocyte‐macrophage colony‐stimulating factor (CSF), macrophage‐CSF, and interleukin‐3 selectively enhance superoxide release triggered by receptor‐mediated agonists . Blood , 79 , 1553 – 1557 ( 1992. ). [PubMed] [Google Scholar]
  • 18).Furukawa , Y. , Ohta , M. , Miura , Y. and Saito , M.Interleukin‐1 producing ability of leukaemia cells and its relationship to morphological diagnosis . Br. J. Haematol. , 65 , 11 – 15 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 19).Ohta , M. , Furukawa , Y. , Ide , C. , Akiyama , N. , Utakoji , T. , Miura , Y. and Saito , M.Establishment and characterization of four human monocytoid leukemia cell lines (JOSK‐I, ‐S, ‐M and ‐K) with capabilities of monocyte‐macrophage lineage differentiation and constitutive production of interleukin 1 . Cancer Res. , 46 , 3067 – 3074 ( 1986. ). [PubMed] [Google Scholar]
  • 20).Furukawa , Y. , Uenoyama , S. , Ohta , M. , Tsunoda , A. , Griffin , J. D. and Saito , M.Transforming growth factor‐β inhibits phosphorylation of the retinoblastoma susceptibility gene product in human monocytic leukemia cell line JOSK‐I . J. Biol. Chem. , 267 , 17121 – 17127 ( 1992. ). [PubMed] [Google Scholar]
  • 21).Arend , W. P. , Joslin , F. G. , Thompson , R. C. and Hannum , C. H.An IL‐1 inhibitor from human monocytes . J. Immunol. , 143 , 1851 – 1858 ( 1989. ). [PubMed] [Google Scholar]
  • 22).Janson , R. W. , Hance , K. R. and Arend , W. P.Production of IL‐1 receptor antagonist by human in vitro‐derived macrophages . J. Immunol. , 147 , 4218 – 4223 ( 1991. ). [PubMed] [Google Scholar]
  • 23).Furukawa , Y. , Ohta , M. , Kasahara , T. , Miura , Y. and Saito , M.Constitutive production of interleukin 1 by human monocytic leukemia cell line JOSK‐I and the production mechanism . Cancer Res. , 47 , 2589 – 2593 ( 1987. ). [PubMed] [Google Scholar]
  • 24).Furukawa , Y. , Ohta , M. , Miura , Y. and Saito , M.Interleukin‐1 derived from human monocytic leukemia cell line JOSK‐I acts as an autocrine growth factor . Biochem. Biophys. Res. Commun. , 147 , 39 – 46 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 25).Arend , W. P. , Smith , M. F. , Janson , R. W. and Joslin , F. G.IL‐1 receptor antagonist and IL‐1β production in human monocytes are regulated differentially . J. Immunol. , 147 , 1530 – 1536 ( 1991. ). [PubMed] [Google Scholar]
  • 26).Poutsiaka , D. D. , Clark , B. D. , Vannter , E. and Dinarello , C. A.Production of interleukin‐1 receptor antagonist and interleukin‐1β by peripheral blood mononuclear cells is differentially regulated . Blood , 78 , 1275 – 1280 ( 1991. ). [PubMed] [Google Scholar]
  • 27).Turner , M. , Chantry , D. , Katsikis , P. , Berger , A. , Brennan , F. M. and Feldmann , M.Induction of interleukin 1 receptor antagonist protein by transforming growth factor‐β . Ear. J. Immunol. , 21 , 1635 – 1639 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 28).Smith , M. F. , Eidlen , D. , Brewer , M. T. , Eisenberg , S. P. , Arend , W. P. and Gutierrez‐Hartmann , A.Human IL‐1 receptor antagonist promoter . J. Immunol. , 149 , 2000 – 2007 ( 1992. ). [PubMed] [Google Scholar]
  • 29).Mangan , D. F. , Welch , G. R. and Wahl , S. M.Lipopoly‐saccharide, tumor necrosis factor‐α, and IL‐1β prevent programmed cell death (apoptosis) in human peripheral blood monocytes . J. Immunol. , 146 , 1541 – 1546 ( 1991. ). [PubMed] [Google Scholar]
  • 30).Mangan , D. F. and Wahl , S. M.Differential regulation of human monocyte programmed cell death (apoptosis) by chemotactic factors and pro‐inflammatory cytokines . J. Immunol. , 147 , 3408 – 3412 ( 1991. ). [PubMed] [Google Scholar]
  • 31).Mangan , D. F. , Robertson , B. and Wahl , S. M.IL‐4 enhances programmed cell death (apoptosis) in stimulated human monocytes . J. Immunol. , 148 , 1812 – 1816 ( 1992. ). [PubMed] [Google Scholar]
  • 32).Lang , R. A. , Metcalf , D. , Cuthbertson , R. A. , Lyons , I. , Stanley , E. , Kelso , A. , Kannourakis , G. , Gonda , T. J. and Dunn , A. R.Transgenic mice expressing a hemopoietic growth factor gene (GM‐CSF) develop accumulation of macrophages, blindness, and a fatal syndrome of tissue damage . Cell , 51 , 675 – 686 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 33).Griffin , J. D. and Lowenberg , B.Clonogenic cells in acute myeloblastic leukemia . Blood , 68 , 1185 – 1195 ( 1986. ). [PubMed] [Google Scholar]
  • 34).Williams , G. T. , Smith , C. A. , Spooncer , E. , Dexter , T. M. and Taylor , D. R.Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis . Nature , 343 , 76 – 79 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 35).Griffin , J. D. , Rambaldi , A. , Vellenga , E. , Young , D. C. , Ostapovicz , D. and Cannistra , S. A.Secretion of inter‐leukin‐1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors . Blood , 70 , 1218 – 1221 ( 1987. ). [PubMed] [Google Scholar]
  • 36).Nakamura , M. , Kanakura , Y. , Furukawa , Y. , Ernst , T. J. and Griffin , J. D.Demonstration of interleukin‐1β transcripts in acute myeloblastic leukemic cells by in situ hybridization . Leukemia , 4 , 466 – 470 ( 1990. ). [PubMed] [Google Scholar]
  • 37).Furukawa , Y. , Ohta , M. , Miura , Y. and Saito , M.Interleukin 1 production by monocytic leukemia cells and its possible role in coagulation abnormalities . Leuk. Res. , 15 , 1133 – 1137 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 38).Young , D. C. , Wagner , K. and Griffin , J. D.Constitutive expression of the granulocyte‐macrophage colony stimulating factor gene in acute myeloblastic leukemia . J. Clin. Invest. , 79 , 100 – 106 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39).Rambaldi , A. , Torcia , M. , Bettoni , S. , Vannier , E. , Barbui , T. , Shaw , A. R. , Dinarello , C. A. and Cozzolino , F.Modulation of cell proliferation and cytokine production in acute myeloblastic leukemia by interleukin‐1 receptor antagonist and lack of its expression by leukemic cells . Blood , 78 , 3248 – 3253 ( 1991. ). [PubMed] [Google Scholar]
  • 40).Yin , M. , Gopal , V. , Banavali , S. , Gartside , P. and Preisler , H.Effects of IL‐1 receptor antagonist on acute myeloid leukemia cells . Leukemia , 6 , 898 – 901 ( 1992. ). [PubMed] [Google Scholar]
  • 41).Estrov , Z. , Kurzrock , R. , Wetzler , M. , Kantarjian , H. , Blake , M. , Harris , D. , Gutterman , J. U. and Talpaz , M.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 . Blood , 78 , 1476 – 1484 ( 1991. ). [PubMed] [Google Scholar]
  • 42).Schiro , R. , Longoni , D. , Rossi , V. , Maglia , O. , Doni , A. , Arsura , M. , Carrara , G. , Masera , G. , Vannier , E. , Dinarello , C. A. , Rambaldi , A. and Biondi , A.Suppression of juvenile chronic myelogenous leukemia colony growth by interleukin‐1 receptor antagonist . Blood , 83 , 460 – 465 ( 1994. ). [PubMed] [Google Scholar]

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