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Leukoregulin up-regulation of tumor cell sensitivity to natural killer and lymphokine-activated killer cell cytotoxicity

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Summary

The present investigation demonstrates that leukoregulin, a cytokine secreted by natural killer (NK) lymphocytes up-regulates the sensitivity of tumor cells to lymphokine-activated killer (LAK) cell cytotoxicity. It has been previously established that leukoregulin increases the sensitivity of sarcoma, carcinoma and leukemia cells to natural killer (NK) cell cytotoxicity. Tumor cells were treated with leukoregulin for 1 h at 37°C and tested for sensitivity to NK and LAK cytotoxicity in a 4-h chromiumrelease assay. NK-resistant Daudi, QGU and C4-1 human cervical carcinoma cells became sensitive to NK cytotoxicity after leukoregulin treatment, and their sensitivity to LAK was increased two- to sixfold. Y-79 retinoblastoma cells, which are moderately sensitive to NK and very sensitive to LAK, became increasingly sensitive (two- to fourfold) to both NK and LAK cell cytotoxicity. Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant interleukin-1 (α and β), recombinant interferon γ, recombinant tumor necrosis factor or combinations of the latter two failed to up-regulate tumor cell sensitivity to NK and LAK cell cytotoxicity. However, treatment with recombinant interferon γ for 16–18 h, GM-CSF and interleukin-1β for 1 h induced a state of target cell resistance to both NK and LAK cell cytotoxicity. Leukoregulin may have an important physiological function in modulating NK and LAK cell cytotoxicity by increasing the sensitivity of target cells to these natural cellular immunocytotoxicity mechanisms.

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References

  1. Anderson TM, Ibayashi Y, Holmes EC, Golub SH (1986) Enhancement of NK activity in tumor infiltrating lymphocytes by recombinant interleukin-2. Surg Forum 37: 392

    Google Scholar 

  2. Anderson TM, Ibayashi Y, Tokuda Y, Colquhoun SD, Holmes EC, Golub SH (1988) Effects of systemic recombinant interleukin-2 on natural killer and lymphokine activated killer activity of human tumor infiltrating lymphocytes. Cancer Res 48: 1180

    Google Scholar 

  3. Auersperg N, Hawryluk A (1962) Chromosome observations on three epithelial cell cultures derived from carcinomas of the human cervix. J Natl Cancer Inst 28: 605

    Google Scholar 

  4. Barnett SC, Evans CH (1986) Leukoregulin-increased plasma membrane permeability and associated ionic fluxes. Cancer Res 46: 2686

    Google Scholar 

  5. Barnett SC, Evans CH (1988) Leukoregulin-induced translocation of protein kinase C activity in K562 cells. Clin Exp Immunol 73: 505

    Google Scholar 

  6. Bloom ET, Babbitt JT (1987) Role of cytokines in the monocyte-mediated augmentation of human natural killer cell activity. Cell Immunol 109: 123

    Google Scholar 

  7. Bloom ET, Babbitt JT, Kawakami K (1986) Monocyte-mediated augmentation of human natural killer cell activity: conditions, monocyte and effector cell characteristics. J Immunol 137: 172

    Google Scholar 

  8. Braakman E, VanTunen A, Meager A, Lucas CJ (1986) IL-2 and IFNγ enhanced natural cytotoxic activity: analysis of the role of different lymphoid subsets and implications for activation routes. Cell Immunol 99: 476

    Google Scholar 

  9. DeBoer K, Kleinman R, Teodorescu M (1981) Identification and separation by bacterial asherence of human lymphocytes that suppress natural cytotoxicity. J Immunol 126: 276

    Google Scholar 

  10. Evans CH (1984) Normal levels of lymphotoxin secretion by freshly isolated and refrigerated human peripheral blood lymphocytes. J Immunol Methods 67: 13

    Google Scholar 

  11. Evans CH, Heinbaugh JA, Ransom JH (1987) Flow cytometric evaluation of leukoregulin as an intrinsic molecular mediator of natural killer lymphocyte cytotoxicity. Lymphokine Res 6: 277

    Google Scholar 

  12. Gersuk GM, Holloway JM, Chang W, Pattengale PK (1986) Inhibition of human natural killer cell activity by plateletderived growth factor. Nat Immun Cell Growth Regul 5: 283

    Google Scholar 

  13. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine-activated killer cell phenomenon: lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 155: 1823

    Google Scholar 

  14. Grimm EA, Ramsey KM, Mazumder A, Wilson DJ, Djeu JY, Rosenberg SA (1983) Lymphokine-activated killer cell phenomenon II. precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymusderived lymphocytes, and natural killer cells. J Exp Med 157: 884

    Google Scholar 

  15. Heiskala M, Timonen T (1987) Effect of interleukin-2 on the inhibition of human natural killer activity by monolayer cells. Cell Immunol 110: 209

    Google Scholar 

  16. Heiskala M, Ylikorkala O, Timonen T (1987) Inhibition of human natural killer activity by monolayers of primary cell cultures. Nat Immun Cell Growth Regul 6: 1

    Google Scholar 

  17. Herberman RB and Ortaldo JR (1981) Natural killer cells: their role in defense against disease. Science 214: 24

    Google Scholar 

  18. Herman J, Dinarello CA, Kew MC, Rabson AR (1985) The role of interleukin 1 (IL1) in tumor-NK cell interactions: correction of defective NK cell activity in cancer patients by treating target cells with IL1. J Immunol 135: 2882

    Google Scholar 

  19. Hoyer M, Meineke T, Lewis W, Zwilling B, Rinehart H (1986) Characterization and modulation of human lymphokine (interleukin-2) activated killer cell induction. Cancer Res 46: 2834

    Google Scholar 

  20. Itoh K, Shiiba K, Shimizu Y, Suzuki R, Kumagai K (1985) Generation of activated killer cells by recombinant interleukin-2 (rIL2) in collaboration with interferon γ (IFN-γ). J Immunol 135: 3124

    Google Scholar 

  21. Kanar MC, Thiele DL, Ostensen M, Lipsky PE (1988) Regulation of human natural killer (NK) cell function: action of killing of an NK-resistant renal cell carcinoma cell line. J Clin Immunol 8: 69

    Google Scholar 

  22. Klein E, Klein G, Nadkarni JS, Nadkarni JJ, Wigzell H, Clifford P (1968) Surface IgM kappa specificity on a Burkitt lymphoma cell in vivo and in derived culture lines. Cancer Res 28: 1300

    Google Scholar 

  23. Kyritsis AP, Tsokos M, Triche TJ, Chader GJ (1986) Retinoblastoma: a primitive tumor with multipotential characteristics. Invest Ophthalmol Vis Sci 27: 1760

    Google Scholar 

  24. Lozzio CB, Lozzio BB (1975) Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome. Blood 45: 321

    Google Scholar 

  25. Mule JJ, Smith CA, Rosenberg SA (1987) Interleukin 4 (B cell stimulatory factor 1) can mediate the induction of lymphokine-activated killer cell activity directed against fresh tumor cells. J Exp Med 166: 792

    Google Scholar 

  26. Nii A, Sone S, Utsugi T, Uanagawa H, Ogura T (1988) Up-and down-regulation of human lymphokine (IL-2)-activated killer cell induction by monocytes, depending on their functional state. Int J Cancer 41: 33

    Google Scholar 

  27. Ostensen ME, Thiele DZ, Lipsky PE (1987) Tumor necrosis factor alpha enhances cytolytic activity of human natural killer cells. J Immunol 138: 4185

    Google Scholar 

  28. Owen-Schaub LB, Gutterman JU, Grimm EA (1988) Synergy of tumor necrosis factor and interleukin 2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor α and interleukin 2 in the generation of human lymphokineactivated killer cell cytotoxicity. Cancer Res 48: 788

    Google Scholar 

  29. Pollack SB (1986) Stimulatory effects of OK-432 on natural killer production and activity. In: Lotzova E, Herberman RB (eds) Natural immunity, cancer and biological response modification. Karger, Basel p 152

    Google Scholar 

  30. Ransom JH, Evans CH (1982) Lymphotoxin enhances the susceptibility of neoplastic and preneoplastic cells to natural killer cell-mediated destruction. Int J Cancer 29: 451

    Google Scholar 

  31. Ransom JH, Evans CH, McCabe RP, Pomato N, Heinbaugh JA, Chin M, Hanna Jr. MG (1985) Leukoregulin, a direct-acting anticancer immunological hormone that is distinct from lymphotoxin and interferon. Cancer Res 45: 851

    Google Scholar 

  32. Santoli D, Trinchieri G, Lief FS (1978) Cell-mediated cytotoxicity against virus-infected target cells in humans. 1: characterization of the effector lymphocytes. J Immunol 121: 526

    Google Scholar 

  33. Shirasawa H, Tomita Y, Sekiya S, Takamizawa H, Simizu B (1987) Integration and transcription of human papillomavirus type 16 and 18 sequences in cell lines derived from cervical carcinomas. J Gen Virol 68: 583

    Google Scholar 

  34. Trinchieri G, Santoli D (1978) Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells: enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis. J Exp Med 147: 1314

    Google Scholar 

  35. Trinchieri G, Perussia B (1984) Human natural killer cells: biologic and pathologic aspects. Lab Invest 50: 489

    Google Scholar 

  36. Uchida A, Vanky F, Klein E (1985) Natural cytotoxicity of human blood lymphocytes and monocytes and their cytotoxic factors: effect of interferon on target cell susceptibility. J Natl Cancer Inst 75: 849

    Google Scholar 

  37. Wright SC, Bonavida B (1983) Studies on the mechanism of natural killer cell-mediated cytotoxicity. iv. Interferon-induced inhibition of NK target cell susceptibility to lysis is due to a defect in their ability to stimulate release of natural killer cytotoxic factors (NKCF). J Immunol 130: 2965

    Google Scholar 

  38. Yagita M, Grimm EA (1986) Inhibition of in vitro LAK generation by OK-432. Cancer Immunol Immunother 23: 207

    Google Scholar 

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  1. Laboratory of Biology, Division of Cancer Etiology, National Cancer Institute, Building 37, Room 2A03, 20892, Bethesda, MD, USA

    Paulette M. Furbert-Harris & Charles H. Evans

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  1. Paulette M. Furbert-Harris
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  2. Charles H. Evans
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Furbert-Harris, P.M., Evans, C.H. Leukoregulin up-regulation of tumor cell sensitivity to natural killer and lymphokine-activated killer cell cytotoxicity. Cancer Immunol Immunother 30, 86–91 (1989). https://doi.org/10.1007/BF01665958

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  • DOI: https://doi.org/10.1007/BF01665958

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