IL-2-Independent Activation of LAK Cells by a Heterodimeric Cytokine, Interleukin-12

  • Maurice K. Gately
  • Aimee G. Wolitzky
  • Phyllis M. Quinn
  • Richard Chizzonite


Interleukin-12 (IL-12) is a heterodimeric cytokine which was originally isolated from cultures of activated human B lymphoblastoid cells and called natural killer cell stimulatory factor (Kobayashi et al., 1989) or cytotoxic lymphocyte maturation factor (Stern et al., 1990). IL-12 has been shown to stimulate the proliferation of activated T cells and natural killer (NK) cells (Gately et al., 1991) and to cause interferon-γ (IFN-γ) production (Kobayashi et al., 1989; Chan et al., 1991) and enhanced NK lytic activity (Kobayashi et al., 1989; Wolf et al., 1991) by resting peripheral blood mononuclear cells (PBMC). IL-12, unlike IL-2, does not cause resting PBMC to proliferate, but it can stimulate enhanced proliferation of PBMC cultured in suboptimal concentrations of IL-2 (Gately et al., 1991). IL-12 is composed of two disulfide-bonded subunits with molecular masses of 35 and 40 kDa (Kobayashi et al., 1989; Stern et al., 1990). The cDNA encoding each of these two subunits has recently been cloned and bioactive recombinant IL-12 (rIL-12) expressed (Gubler et al., 1991; Wolf et al., 1991). Coexpression of the two subunits is required for biologically active IL-12 to be produced (Gubler et al., 1991: Wolf et al., 1991).


Peripheral Blood Mononuclear Cell Suboptimal Concentration Peripheral Blood Mononuclear Cell Proliferation Heterodimeric Cytokine Hydrocortisone Sodium Succinate 
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  1. Alderson MR, Sassenfeld HM, Widmer MB (1990): Interleukin 7 enhances cytolytic T lymphocyte generation and induces lymphokine-activated killer cells from human peripheral blood. J Exp Med 172: 577 - 587CrossRefGoogle Scholar
  2. Alegre M-L, Vandenabeele P, Depierreux M, Florquin S, Deschodt-Lanckman M, Flamand V, Moser M, Leo O, Urbain J, Fiers W, Goldman M (1991): Cytokine release syndrome induced by the 145-2C11 anti-CD3 monoclonal antibody in mice: Prevention by high doses of methylprednisolone. J Immunol 146: 1184 - 1191Google Scholar
  3. Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospisil M, Young HA, Wolf SF, Young D, Clark SC, Trinchieri G (1991): Induction of interferon; production by natural killer cell stimulatory factor: Characterization of the responder cells and synergy with other inducers. J Exp Med 173: 869 - 879CrossRefGoogle Scholar
  4. Chizzonite R, Truitt T, Podlaski FJ, Wolitzky AG, Quinn PM, Nunes P, Stern AS, Gately MK (1991): IL-12: Monoclonal antibodies specific for the 40-kDa subunit block receptor binding and biologic activity on activated human lymphoblasts. J Immunol 147: 1548 - 1556Google Scholar
  5. Crump WL III, Owen-Schaub LB, Grimm EA (1989): Synergy of human recombinant interleukin 1 with interleukin 2 in the generation of lymphokine-activated killer cells. Cancer Res 49: 149 - 153Google Scholar
  6. Daynes RA, Araneo BA (1989): Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4. Eur J Immunol 19: 2319 - 2325CrossRefGoogle Scholar
  7. Ellis TM, McKenzie RS, Simms PE, Helfrich BA, Fisher RI (1989): Induction of human lymphokine-activated killer cells by IFN-a and IFN. J Immunol 143: 4282 - 4286Google Scholar
  8. Espevik T, Figari IS, Ranges GE, Palladino MA, Jr (1988): Transforming growth factor-β, (TGF-β,) and recombinant human tumor necrosis factor-a reciprocally regulate the generation of lymphokine-activated killer cell activity. Comparison between natural porcine platelet-derived TGF-β, and TGF-β,, and recombinant human TGF-β,. J Immunol 140: 2312 - 2316Google Scholar
  9. Gately MK, Desai BB, Wolitzky AG, Quinn PM, Dwyer CM, Podlaski FJ, Familletti PC, Sinigaglia F, Chizzonite R, Gubler U, Stern AS (1991): Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol 147: 874 - 882Google Scholar
  10. Gately MK, Glaser M, Dick SJ, Mettetal RW, Jr, Kornblith PL (1982): In vitro studies on the cell-mediated immune response to human brain tumors. I. Requirement for third-party stimulator lymphocytes in the induction of cell-mediated cytotoxic responses to allogeneic cultured gliomas. JNCI 69: 1245 - 1254Google Scholar
  11. Gillis S, Crabtree GR, Smith KA (1979): Glucocorticoid-induced inhibition of T cell growth factor production. I. The effect on mitogen-induced lymphocyte proliferation. J Immunol 123: 1624 - 1631Google Scholar
  12. Gubler U, Chua AO, Schoenhaut DS, Dwyer CM, McComas W, Motyka R, Nabavi N, Wolitzky AG, Quinn PM, Familletti PC, Gately MK (1991): Coexpression of two distinct genes is required to generate secreted, bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci USA 88: 4143 - 4147CrossRefGoogle Scholar
  13. Kawakami Y, Custer MC, Rosenberg SA, Lotze MT (1989): IL-4 regulates IL-2 induction of lymphokine-activated killer activity from human lymphocytes. J Immunol 142: 3452 - 3461Google Scholar
  14. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G (1989): Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biological effects on human lymphocytes. J Exp Med 170: 827 - 845CrossRefGoogle Scholar
  15. Mier JW, Vachino G, Klempner MS, Aronson FR, Noring R, Smith S, Brandon EP, Laird W, Atkins MB (1990): Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: Prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects. Blood 10: 1933 - 1940Google Scholar
  16. Naume B, Shalaby R, Lesslauer W, Espevik T (1991): Involvement of the 55- and 75-kDa tumor necrosis factor receptors in the generation of lymphokine-activated killer cell activity and proliferation of natural killer cells. J Immunol 146: 3045 - 3048Google Scholar
  17. 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 a and interleukin 2 in the generation of human lymphokine-activated killer cell cytotoxicity. Cancer Res 48: 788 - 792Google Scholar
  18. Stern AS, Podlaski FJ, Hulmes JD, Pan YE, Quinn PM, Wolitzky AG, Familletti PC, Stremlo DL, Truitt T, Chizzonite R, Gately MK (1990): Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Nati Acad Sci USA 87: 6808 - 6812CrossRefGoogle Scholar
  19. Stotter H, Custer MC, Bolton ES, Guedez L, Lotze MT (1991): IL-7 induces human lymphokine-activated killer cell activity and is regulated by IL-4. J Immunol 146: 150 - 155Google Scholar
  20. Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Ferenz C, Hewick RM, Kelleher K, Herrmann SH, Clark SC, Azzoni L, Chan SH, Trinchieri G, Perussia B (1991): Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol 146: 3074 - 3081Google Scholar

Copyright information

© Birkhäuser Boston 1993

Authors and Affiliations

  • Maurice K. Gately
  • Aimee G. Wolitzky
  • Phyllis M. Quinn
  • Richard Chizzonite

There are no affiliations available

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