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. 1993 Apr;84(4):431–437. doi: 10.1111/j.1349-7006.1993.tb00154.x

Interleukin‐2 Prevents Programmed Cell Death in Adult T‐Cell Leukemia Cells

Hiroyuki Tsuda 1,2,✉, Ren‐Wei Huang 2, Kiyoshi Takatsuki 2
PMCID: PMC5919303  PMID: 8514610

Abstract

Adult T‐cell leukemia (ATL) is a prototype of the lymphoma/leukemia syndromes involving immunologically mature T‐lymphocytes. The first retrovirus described in humans, HTLV‐I, is causally related to the disease. In this study, we examined whether ATL cells die in vitro through programmed cell death (PCD), which has been shown to occur in cells affected by several other acute and chronic Icukcmias. When ATL cells from peripheral blood were cultured in serum‐free complete medium, a substantial proportion of them spontaneously died by PCD. After 48 h of culture, approximately 30% of the total DNA was fragmented. Electrophoresis indicated that the DNA of the ATL cells had been cleaved into regular oligonucleosome fragments each comprising approximately 180–200 base pairs. This process was significantly promoted by methylprednisolone and the protein kinase A (PKA) activator Sp‐cAMPS in at least some cases. Since all ATL cells possess interleukin‐2 receptors on the cell membrane, the effect of IL‐2 on spontaneous PCD was assessed. PCD after 48 h of culture was inhibited by 30–50% by 100 U/ml interleukin‐2 (IL‐2). This effect of IL‐2 to prevent spontaneous PCD was dose‐ and time‐dependent. These findings suggest that the viability of ATL cells in vivo is regulated positively and negatively by intrinsic IL‐2, glucocorticoid and regulators of PKA activity. Furthermore, the process of cell death may be involved in the development of the disease.

Keywords: Apoptosis, Programmed cell death, Adult T‐cell leukemia, Interleukin‐2

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REFERENCES

  • 1. ) Catovsky , D. and Foa , R. “ The Lymphoid Leukemias ” ( 1990. ). Butterworth; , London . [Google Scholar]
  • 2. ) Takatsuki , K. , Yamaguchi , K. and Hattori , T.Adult T‐cell leukemia/lymphoma . In “ Retrovirus Biology and Human Disease ,” ed. Gallo R. C. and Wong‐Staal F. , pp. 147 – 159 ( 1990. ). Marcel Dekker; , New York . [Google Scholar]
  • 3. ) Wyllie , A. H. , Kerr , J. F. R. and Currie , A. R.Cell death: the significance of apoptosis . Int. Rev. Cytol , 68 , 251 – 356 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) McConkey , D. J. , Orrenius , S. and Jondal , M.Cellular signalling in programmed cell death (apoptosis) . Immitnol. Today , 11 , 120 – 121 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Arends , M. J. , Morris , R. G. and Wyllie , A. H.Apoptosis: the role of the endonuclease . Am. J. Pathol. , 136 , 593 – 608 ( 1990. ). [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Raff , C. M.Social controls on cell survival and cell death . Nature , 356 , 397 – 399 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Duvall , E. and Wyllie , A. H.Death and the cell . Immunol. Today , 7 , 115 – 119 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Kerr , J. F. R. , Searle , J. , Harmon , B. V. and Bishop , C. J.Apoptosis . In “ Perspectives on Mammalian Cell Death ,” ed. Potten C. S. , p. 93 ( 1987. ). Oxford University Press; , New York . [Google Scholar]
  • 9. ) Tsuda , H. and Takatsuki , K.Correlation of aberrant proliferation with T‐cell growth factor in adult T‐cell leukemia cells . Haematol. Oncol. , 1 , 177 – 185 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Uchiyama , T. , Hori , T. , Tsudo , M. , Wano , Y. , Umadome , H. , Tamori , S. , Yodoi , J. , Maeda , M. , Sawami , H. and Uchino , H.Interleukin‐2 receptor (Tac antigen) expressed on adult T‐cell leukemia cells . J. Clin. Invest. , 76 , 446 – 453 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. ) Uchiyama , T. , Kamio , M. , Kodaka , T. , Tamori , S. , Fukuhara , S. , Amakawa , R. , Uchino , H. and Araki , K.Leukemic cells from some adult T‐cell leukemia patients proliferate in response to interleukin‐4 . Blood , 72 , 1182 – 1186 ( 1988. ). [PubMed] [Google Scholar]
  • 12. ) Rothemel , J. D. , Botelho , and Parker , L. H.A mechanistic and kinetic analysis of the interactions of the diasteroisomers of adenosine 3′,5′‐(cyclic)phosphorothioate . Biochem. J. , 251 , 757 – 762 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Sellins , K. S. and Cohen , J. J.Gene induction by 7‐irradiation leads to DNA fragmentation in lymphocytes . J. Immunol , 139 , 3199 – 3206 ( 1987. ). [PubMed] [Google Scholar]
  • 14. ) Burton , K.A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid . Biochem. J. , 62 , 315 – 323 ( 1956. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Mangan , D. F. , Welch , G. R. and Wahl , S. M.Lipopolysaccharide, tumor necrosis factor‐a and IL‐1β prevent programmed cell death (apoptosis) in human peripheral blood monocytes . J. Immunol. , 146 , 1541 – 1546 ( 1991. ). [PubMed] [Google Scholar]
  • 16. ) Lannote , M. , Riviere , J. B. , Hermouet , C. , Houce , C. , Vintermyr , O. K. , Gjertsen , B. T. and Doskeland , S. O.Programmed cell death (apoptosis) is induced rapidly and with positive cooperativity by activation of cyclic adenosine monophosphate‐kinase I in a myeloid leukemia cell line . J. Cell Physiol. , 146 , 73 – 80 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) McConkey , D. J. , Orrenius , S. and Jondal , M.Agents that elevate cAMP stimulate DNA fragmentation in thymocytes . J. Immunol. , 145 , 1227 – 1230 ( 1990. ). [PubMed] [Google Scholar]
  • 18. ) Kizaki , H. , Suzuki , K. , Tadakuma , T. and Ishimura , Y.Adenosine receptor‐mediated accumulation of cyclic AMP induced T‐lymphocyte death through internucleosomal DNA cleavage . J. Biol. Chem. , 265 , 5280 – 5284 ( 1990. ). [PubMed] [Google Scholar]
  • 19. ) Dealtry , G. B , Naylor , M. S. , Fiers , W. and Balkwill , F. R.DNA fragmentation and cytotoxicity caused by tumor necrosis factor is enhanced by interferon‐γ . Eur. J. Immunol. , 17 , 689 – 693 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Nieto , M. A. , Gonzales , A. , Lopez‐Rivas , A. , Diaz‐Espada , F. and Gambon , F.IL‐2 protects against anti‐CD3‐induced cell death in human medullary thymocytes . J. Immunol. , 145 , 1364 – 1368 ( 1990. ). [PubMed] [Google Scholar]
  • 21. ) Fernandez‐Ruiz , E. , Rebollo , A. , Nieto , M. A. , Sanz , E. , Somoza , C. , Ramirez , F. , Lopez‐Rivas , A. and Silva , A.IL‐2 protects T cell hybrids from the cytolytic effect of glucocorticoids — synergistic effect of IL‐2 and Dexa‐methasone in the induction of high‐affinity IL‐2 receptors . J. Immunol. , 143 , 4146 – 4151 ( 1989. ). [PubMed] [Google Scholar]
  • 22. ) Lenardo , M. J.Interleukin‐2 programs mouse αβ T lymphocytes for apoptosis . Nature , 353 , 858 – 861 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Yamaguchi , Y. , Suda , T. , Ohtam , S. , Tominaga , K. , Miura , Y. and Kasahara , T.Analysis of the survival of mature human eosinophils: interleukin‐5 prevents apoptosis in mature human eosinophils . Blood , 78 , 2542 – 2547 ( 1991. ). [PubMed] [Google Scholar]
  • 24. ) Yoish‐Rouach , E. , Resnitzky , D. , Lotem , J. , Sachs , L. , Kimch , A. and Oren , M.Wild‐type p53 induces apoptosis of myeloid leukemic cells that is inhibited by interleukin‐6 . Nature , 352 , 345 – 347 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Williams , G. T. , Smith , C. A. , Spooncer , E. , Dexter , T. M. , and Taylor , D. R.Hematopoietic colony stimulating factors promote cell survival by suppressing apoptosis . Nature , 343 , 76 – 79 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Koury , M. J. and Bondurant , M. C.Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells . Science , 248 , 378 – 381 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Rodriguez‐Tarduchy , G. , Collins , M. and Lopez‐Rivas , A.Regulation of apoptosis in interleukin‐3‐dependent hemopoietic cells by interleukin‐3 and calcium ionophores . EMBO J. , 9 , 2997 – 3002 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. ) Debatin , K‐M. , Goldmann , C. K. , Bamford , R. , Waldmann , T. A. and Krammer , P. H.Monoclonal‐antibody‐mediated apoptosis in adult T‐cell leukemia . Lancet , 335 , 497 – 500 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Mills , G. M. , Girard , P. , Grinstein , S. and Gelfand , E. W.Interleukin‐2 induces proliferation of T lymphocyte mutant lacking protein kinase C . Cell , 55 , 91 – 100 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Valge , V. E. , Wong , J. G. and Datlof , B. M.Protein kinase C is required for responses to T cell receptor ligands but not to interleukin 2 in T cells . Cell , 55 , 101 – 112 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Ellis , H. M. and Horvitz , H. R.Genetic control of programmed cell death in the nematode C. elegans . Cell , 44 , 817 – 829 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Hengartner , M. O. , Ellis , R. E. and Horvitz , H. R.Caenorhabditis elegans gene ced‐9 protects cells from programmed cell death . Nature , 356 , 494 – 499 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Hockenbery , D. , Nunez , G. , Milliman , C. , Schreiber , R. D. and Korsmeyer , S.bc1‐2 is an inner mitochondrial membrane protein that blocks programmed cell death . Nature , 348 , 334 – 336 ( 1990. ). [DOI] [PubMed] [Google Scholar]

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