Mechanisms of superior anti-tumor cytotoxic response of interleukin 15-induced lymphokine-activated killer cells.
Interleukin (IL) 15 is one of the main cytokines controlling cytotoxic lymphocyte survival and growth. Despite its receptor and functional similarity to IL-2, IL-15 affects a wider target cell population and utilizes different mechanisms in cell activation. The role of IL-15 in lymphokine-activated killer (LAK) cell generation in vitro and potential mechanisms of cytotoxicity compared with equivalent low concentration of IL-2 with or without mitogens (phytohemoglutinin (PHA) and anti-CD3 antibody) have been investigated in this study. IL-15 treatment resulted in moderate cell proliferation over 7 days, whereas IL-2 treatment was associated with decreased cell numbers. Unlike IL-2 in combination with mitogens, IL-15 caused increases in both cytotoxic T lymphocytes (CTL) and CD56 LAK cells, particularly cytokine-induced killer and cytolytic natural killer T-cell (CNK-T) subpopulations, which are known to be highly effective in cytotoxicity. IL-15 also increased overall perforin and tumor necrosis factor-alpha expression and more prominently in CTLs. Consequently, IL-15 resulted in superior cytotoxicity against two different NK-sensitive (human K-562 and murine YAC-1) and LAK-sensitive (human Daudi and Raji) cell lines compared with other cytokine combinations. There was also no contribution of mitogens to IL-2-induced cytotoxicity. In conclusion, IL-15 at the concentration of 10 ng/mL used in this study causes moderate proliferation and superior cytotoxicity of LAK cells in vitro that was associated with induction of a specific LAK cell subpopulation profile and related cellular killing mechanisms. These results are encouraging for potential use of IL-15 as part of immunotherapy.
Ozdemir
Oner
O
Division of Hematology/Oncology, Children's Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201-2196, USA.
Ravindranath
Yaddanapudi
Y
Savaşan
Süreyya
S
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D053804:Granzymes; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D054353:Perforin; D010835:Phytohemagglutinins / Q000494:pharmacology; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D019409:Interleukin-15; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D010835:Phytohemagglutinins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases