title: PGC-1α-Dependent Mitochondrial Adaptation Is Necessary to Sustain IL-2-Induced Activities in Human NK Cells.
abstract: Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in antitumor defense reactions. NK cell effector functions are critically dependent on cytokines and metabolic activity. Among various cytokines modulating NK cell function, interleukin-2 (IL-2) can induce a more potent cytotoxic activity defined as lymphokine activated killer activity (LAK). Our aim was to determine if IL-2 induces changes at the mitochondrial level in NK cells to support the bioenergetic demand for performing this enhanced cytotoxic activity more efficiently. Purified human NK cells were cultured with high IL-2 concentrations to develop LAK activity, which was assessed by the ability of NK cells to lyse NK-resistant Daudi cells. Here we show that, after 72 h of culture of purified human NK cells with enough IL-2 to induce LAK activity, both the mitochondrial mass and the mitochondrial membrane potential increased in a PGC-1α-dependent manner. In addition, oligomycin, an inhibitor of ATP synthase, inhibited IL-2-induced LAK activity at 48 and 72 h of culture. Moreover, the secretion of IFN-γ from NK cells with LAK activity was also partially dependent on PGC-1α expression. These results indicate that PGC-1α plays a crucial role in regulating mitochondrial function involved in the maintenance of LAK activity in human NK cells stimulated with IL-2.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Sergio Livingstone 1007, Independencia, 8380492 Santiago, Chile.
authors.forename: Dante
authors.identifier: 0000-0002-4804-0920
authors.initials: D
authors.lastname: Miranda
authors.affiliation: Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Avenida Libertador Bernardo O'Higgins 3363, 9170022 Santiago, Chile.
authors.forename: Claudia
authors.initials: C
authors.lastname: Jara
authors.affiliation: Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Avenida Libertador Bernardo O'Higgins 3363, 9170022 Santiago, Chile.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ibañez
authors.affiliation: Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Avenida Libertador Bernardo O'Higgins 3363, 9170022 Santiago, Chile.
authors.forename: Viviana
authors.initials: V
authors.lastname: Ahumada
authors.affiliation: Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Avenida Libertador Bernardo O'Higgins 3363, 9170022 Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Acuña-Castillo
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Sergio Livingstone 1007, Independencia, 8380492 Santiago, Chile.
authors.forename: Adrian
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Avenida Libertador Bernardo O'Higgins 3363, 9170022 Santiago, Chile.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Córdova
authors.affiliation: Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Avenida Libertador Bernardo O'Higgins 3363, 9170022 Santiago, Chile.
authors.forename: Margarita
authors.identifier: 0000-0002-6268-1118
authors.initials: M
authors.lastname: Montoya
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism* / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D009840:Oligomycins / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D009840:Oligomycins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D007371:Interferon-gamma; D025261:Mitochondrial Proton-Translocating ATPases