Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1994 Jul;38(4):281–286. doi: 10.1007/BF01533521

Induction of lymphokine-activated killer activity in mice by prothymosin α

Constantin N Baxevanis 1, Angelos D Gritzapis 1, George V Z Dedoussis 1, Nikolaos G Papadopoulos 1, Orestes Tsolas 2, Michael Papamichail 1,✉
PMCID: PMC11038266  PMID: 8168124

Abstract

We have recently demonstrated that prothymosin α (ProTα) when administered intraperitoneally (i.p.) protects DBA/2 mice against the growth of syngeneic leukemic L1210 cells through the induction of tumoricidal peritoneal cells producing high levels of tumor necrosis factor α (TNFα) [Papanastasiou et al. (1992) Cancer Immunol Immunother 35: 145]. In this report we tested further immunological alterations that may be caused by the administration of ProTα in vivo. We demonstrate that i.p. injections of ProTα enhance natural killer (NK) cell activity and induce lymphokine-activated (LAK) activity in vivo. Thus, splenocytes from ProTα-treated DBA/2 animals exhibited significantly higher cytotoxic activity (up to threefold) against the NK-sensitive YAC cell line and the NK-resistant P815 and L1210 syngeneic tumor cells, as compared to splenocytes from syngeneic control mice. The enhancement of the cytotoxic profile of DBA/2 splenocytes was associated with increased percentages of CD8+ cells, NK cells and activated CD3+ cells. The ProTα-induced effect persisted for 30 days after the end of the ProTα treatment period and returned to normal levels 20 days later. SPlenocytes from non-treated DBA/2 animals generated high NK and LAK activities in response to ProTα in vitro. The ProTα-induced NK an LAK activities reached 84% and 75% respectively of what was obtained with interleukin-2 (IL-2). High concentrations of TNFα and IL-2 were generated in response to ProTα in LAK cultures. These findings suggest that ProTα may provide an overall protective effect against tumor growth in vivo through induction of NK and LAK activities possibly indirectly via the production of IL-2 and TNFα in the spleen, peritoneal cavity and probably other lymphoid organs.

Key words: Prothymosin α, NK and LAK activity, TNFα, IL-2

Footnotes

This work was supported by a CEC grant to M. Papamichail

References

  • 1.Baxevanis CN, Nagy ZA, Klein J. A novel type of T−T cell interaction remove the requirement for I−B region in the H-2 complex. Proc Natl Acad Sci USA. 1981;78:3809. doi: 10.1073/pnas.78.6.3809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Baxevanis CN, Reclos GJ, Papamichail M, Tsokos GC. Prothymosin α restores the depressed autologous and allogeneic mixed lymphocyte reaction in patients with systemic lupus erythematosus. Immunopharmacol Immunotoxicol. 1987;9:429. doi: 10.3109/08923978709035224. [DOI] [PubMed] [Google Scholar]
  • 3.Baxevanis CN, Reclos GJ, Paneerselvam M, Papamichail M. Enhancement of human T lymphocyte functions by prothymosin α. I. Augmentation of mixed lymphocyte culture reactions and soluble protein-induced-proliferative responses. Immunopharmacology. 1988;15:73. doi: 10.1016/0162-3109(88)90054-9. [DOI] [PubMed] [Google Scholar]
  • 4.Baxevanis CN, Reclos GJ, Papamichail M. Decreased HLA-DR expression on monocytes causes impaired suppressor cell activity in multiple sclerosis. J Immunol. 1990;144:4166. [PubMed] [Google Scholar]
  • 5.Baxevanis CN, Thanos D, Reclos GJ, Anastasopoulos E, Tsokos GL, Papamatheakis J, Papamichail M. Prothymosin α enhances human and murine major histocompatibility complex class II surface antigen expression and mRNA accumulation. J Immunol. 1992;148:1979. [PubMed] [Google Scholar]
  • 6.Baxevanis CN, Reclos GJ, Papamichail M. Prothymosin α restores depressed allogeneic cell-mediated lympholysis and natural-killer-cell activity in patients with cancer. Int J Cancer. 1993;53:264. doi: 10.1002/ijc.2910530216. [DOI] [PubMed] [Google Scholar]
  • 7.Chouaib S, Bertoglio G, Blay J-Y, Marchid-Fournigault C, Fradelizi D. Generation of lymphokine-activated killer cells: synergy between tumor necrosis factor and interleukin 2. Proc Natl Acad Sci USA. 1988;85:6875. doi: 10.1073/pnas.85.18.6875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Eschenfeldt WH, Berger SL. The human prothymosin α gene is polymorphic and induced upon growth stimulation: evidence using a cloned cDNA. Proc Natl Acad Sci USA. 1986;83:9. doi: 10.1073/pnas.83.24.9403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Fujiwara T, Grimm EA. Regulation of lymphokine-activated killer cell induction by human recombinant IL-1 receptor antagonist. J Immunol. 1992;148:2941. [PubMed] [Google Scholar]
  • 10.Gallacher G, Stimson WH, Findlay J, Al-Azzawi F. Interleukin-6 enhances the induction of human lymphokine-activated killer cells. Cancer Immunol Immunother. 1990;31:49. doi: 10.1007/BF01742495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Gately M, Wolitzky AG, Quinn PM, Chizzonite R. Regulation of human cytolytic lymphocyte responses by interleukin-12. Cell Immunol. 1992;143:127. doi: 10.1016/0008-8749(92)90011-d. [DOI] [PubMed] [Google Scholar]
  • 12.Goodall GJ, Dominquez F, Horecker BL. Molecular cloning of cDNA for human prothymosin α. Proc Natl Acad Sci USA. 1986;83:8926. doi: 10.1073/pnas.83.23.8926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Haritos AA, Goodall GJ, Horecker BL. Prothymosin α: isolation and properties of the major immunoreactive form of thymosin α1 in rat thymus. Proc Natl Acad Sci USA. 1984;81:1008. doi: 10.1073/pnas.81.4.1008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Haritos AA, Tsolas O, Horecker BL. Distribution of prothymosin α in rat tissues. Proc Natl Acad Sci USA. 1984;81:1391. doi: 10.1073/pnas.81.5.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Haritos AA, Salvin BB, Blacher R, Stein S, Horecker BL. Parathymosin α: a peptide from rat tissues with structural homology to prothymosin α. Proc Natl Acad Sci USA. 1985;82:1050. doi: 10.1073/pnas.82.4.1050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Jackson AM, Hawkyard SJ, Prescott S, Ricchie AW, James K, Chisholm GD. An investigation of factors influencing the in vitro induction of LAK activity against a variety of human bladder cell lines. J Urol. 1992;147:207. doi: 10.1016/s0022-5347(17)37198-7. [DOI] [PubMed] [Google Scholar]
  • 17.Lotzova E. Analysis of effector mechanisms in cancer. Curr Opin Immunol. 1989;1:904. doi: 10.1016/0952-7915(89)90069-1. [DOI] [PubMed] [Google Scholar]
  • 18.Lotzova E, Herberman RB. Reassessment of LAK phenomenology: a review. Nat Immun Cell Growth Regul. 1987;6:109. [PubMed] [Google Scholar]
  • 19.Matossian-Rogers A, Browne C, Turkish M, O'Byrne P, Festenstein H. Tumor necrosis factor-alpha enhances the cytolytic and cytostatic capacity of interleukin-2 activated killer cells. Br J Cancer. 1989;59:573. doi: 10.1038/bjc.1989.116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Mule JJ, Custer MC, Travis WD, Rosenberg SA. Cellular mechanisms of the antitumor activity of recombinant IL-6 in mice. J Immunol. 1992;148:2622. [PubMed] [Google Scholar]
  • 21.Mule JJ, Marcus SG, Yang JC, Weber JS, Rosenberg SA. Clinical application of IL-6 in cancer therapy. Res Immunol. 1992;143:777. doi: 10.1016/0923-2494(92)80023-e. [DOI] [PubMed] [Google Scholar]
  • 22.Naume B, Gately M, Espevik T. A comparative study of IL-12-, IL-2-, and IL-7-induced effects on immunomagnetically purified CD56+ NK cells. J Immunol. 1992;148:2429. [PubMed] [Google Scholar]
  • 23.Pan L-X, Haritos AA, Wideman J, Komiyama T, Chang M, Stein S, Salvin SB, Horecker BL. Human prothymosin α: amino acid sequence and immunologic properties. Arch Biochem Biophys. 1986;250:197. doi: 10.1016/0003-9861(86)90717-4. [DOI] [PubMed] [Google Scholar]
  • 24.Papamichail M, Baxevanis CN. Gamma-interferon enhances the cytotoxic activity of interleukin-2-induced peripheral blood lymphocyte (LAK) cells, tumor infiltrating lymphocytes (TIL), and effusion associated lymphocytes. J Chemother. 1992;4:387. doi: 10.1080/1120009x.1992.11739197. [DOI] [PubMed] [Google Scholar]
  • 25.Papanastasiou M, Baxevanis CN, Papamichail M. Promotion of murine antitumor activity by prothymosin α treatment. I. Induction of tumoricidal peritoneal cells producing high levels of tumor necrosis factor α. Cancer Immunol Immunother. 1992;35:145. doi: 10.1007/BF01741862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Reclos GC, Baxevanis CN, Sfagos C, Papageorgiou C, Tsokos GC, Papamichail M. Multiple sclerosis. II. Effects of prothymosin α on the autologous and allogeneic MLR in patients with multiple sclerosis. Clin Exp Immunol. 1987;70:336. [PMC free article] [PubMed] [Google Scholar]
  • 27.Reiter Z, Ozes ON, Blatt LM, Taylor MW. A dual antitumor effect of a combination of interferon-α or interleukin-2 and 5-fluorouracil on natural killer (NK) cell-mediated cytotoxicity. Clin Immunol Immunopathol. 1992;62:103. doi: 10.1016/0090-1229(92)90029-n. [DOI] [PubMed] [Google Scholar]
  • 28.Smyth MJ, Ortaldo JR. Comparison of the effect of IL-2 and IL-6 on the lytic activity of purified human peripheral blood large granular lymphocytes. J Immunol. 1991;146:1380. [PubMed] [Google Scholar]
  • 29.Takai Y, Wong GG, Clark SC, Burkoff SJ, Herrman SH. B-cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes. J Immunol. 1988;140:508. [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES