title: TNF-alpha and IFN-gamma reverse IL-4 inhibition of lymphokine-activated killer cell function.
abstract: Recombinant IL-4 inhibits IL-2-induced lymphokine-activated killer (LAK) cell development of PBMC. We evaluated the effect of various cytokines in reversing IL-4-mediated LAK inhibition. PBMC were cultured in IL-2 (10-1000 u/ml) with or without IL-4 (2-100 u/ml) and tested for cytotoxicity against the NK-sensitive K562 cells and NK-resistant UCLA-SO-M14 cells. Addition of IL-4 at the beginning of culture suppresses LAK activity in a dose-dependent fashion. Addition of IFN-gamma or TNF-alpha partially reverses IL-4-mediated inhibition (30-100%) in a dose-dependent fashion. IFN-gamma and TNF-alpha must be added within the first 24 hr of initiating culture in order to reverse IL-4 inhibition. Furthermore, IFN-gamma and TNF-alpha are most effective at reversing IL-4 inhibition at low concentrations of IL-2 (less than 100 u/ml). Addition of other IL-2-induced cytokines such as GM-CSF (50 u/ml), M-CSF (250 u/ml), and IFN-alpha (10-10,000 u/ml) fails to reverse IL-4 inhibition. In addition to suppression of LAK induction, IL-4 also inhibits IL-2-induced IFN-gamma and TNF-alpha protein production in PBMC. The reversal of IL-4-mediated LAK inhibition by TNF-alpha and IFN-gamma may therefore be due to resupply of these endogenously suppressed cytokines.
authors.affiliation: Division of Surgical Oncology, UCLA School of Medicine, Los Angeles, California 90024.
authors.forename: S G
authors.initials: SG
authors.lastname: Swisher
authors.forename: J S
authors.initials: JS
authors.lastname: Economou
authors.forename: E C
authors.initials: EC
authors.lastname: Holmes
authors.forename: S H
authors.initials: SH
authors.lastname: Golub
mesh_terms: D003115:Colony-Stimulating Factors / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology* / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D016173:Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
chemical_list: D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007370:Interferon Type I; D007376:Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor