title: Cooperation of natural killer cell stimulatory factor/interleukin-12 with other stimuli in the induction of cytokines and cytotoxic cell-associated molecules in human T and NK cells.
abstract: The ability of natural killer cell stimulatory factor/interleukin-12 (IL-12) to induce cytokines other than IFN-gamma from both T and NK cells was studied. Both the direct effect of IL-12 and the cooperation between IL-12 and other cytokine inducers such as IL-2, phorbol diesters, and receptor antibodies were evaluated. It was found that IL-12 induces mRNA accumulation and production of GM-CSF and TNF-alpha from both T and NK cells and, as tested on NK cells only, induces M-CSF mRNA accumulation. Compared with cytokine inducers, IL-12 ability to induce IFN-gamma production was severalfold higher than its ability to induce GM-CSF or TNF-alpha. Likewise, the synergistic effect of IL-12 with the other stimuli to induce IFN-gamma was stronger than that observed in the case of GM-CSF or TNF-alpha. The IL-12-mediated enhancement of NK cytotoxicity is accompanied by an increased accumulation of mRNA for at least two genes encoding cytotoxic cell granule-associated proteins, the serine esterase granzyme B and the pore-forming protein perforin. IL-12 induction of perforin mRNA accumulation was not synergistic with either IL-2 or anti-CD16 stimulation, whereas granzyme B mRNA accumulation, induced by IL-2 or anti-CD16 stimulation, was slightly potentiated by IL-12. Thus, although IFN-gamma production is probably one of the most physiologically relevant effects of IL-12, induction of other cytokines by IL-12 in the presence of other inflammatory or immune stimuli may have a role in the in vivo functions of IL-12. The observation that both the IL-12-mediated enhancement of NK cell-mediated cytotoxicity and the increased expression of genes encoding cytotoxic cell granule-associated proteins were not cooperative with the effect of other NK cell activators suggests that the effect of IL-12 on cytotoxic cells is in part independent from that of other stimuli regulating the functions of these cells.
authors.affiliation: Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104.
authors.forename: M
authors.initials: M
authors.lastname: Aste-Amezaga
authors.forename: A
authors.initials: A
authors.lastname: D'Andrea
authors.forename: M
authors.initials: M
authors.lastname: Kubin
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
mesh_terms: D017252:CD3 Complex; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D018664:Interleukin-12; D007376:Interleukin-2 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D007376:Interleukin-2; D007378:Interleukins; D012333:RNA, Messenger; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate