Research Article PGC-1-Dependent Mitochondrial Adaptation Is Necessary to Sustain IL-2-Induced Activities in Human NK Cells Dante Miranda, 1 Claudia Jara, 2 Jorge Ibañez, 2 Viviana Ahumada, 2 Claudio Acuña-Castillo, 2 Adrian Martin, 1 Alexandra Córdova, 2 and Margarita Montoya 2 1 Department of Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Sergio Livingstone 1007, Independencia, 8380492 Santiago, Chile 2 Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Avenida Libertador Bernardo O’Higgins 3363, 9170022 Santiago, Chile Correspondence should be addressed to Margarita Montoya; margarita.montoya@usach.cl Received 3 November 2015; Revised 2 February 2016; Accepted 24 May 2016 Academic Editor: Jagadeesh Bayry Copyright © 2016 Dante Miranda et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in antitumor defense reactions. NK cell efector 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 defned 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 efciently. Purifed 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, afer 72 h of culture of purifed human NK cells with enough IL-2 to induce LAK activity, both the mitochondrial mass and the mitochondrial membrane potential increased in a PGC-1-dependent manner. In addition, oligomycin, an inhibitor of ATP synthase, inhibited IL-2-induced LAK activity at 48 and 72h of culture. Moreover, the secretion of IFN- from NK cells with LAK activity was also partially dependent on PGC-1 expression. Tese results indicate that PGC-1 plays a crucial role in regulating mitochondrial function involved in the maintenance of LAK activity in human NK cells stimulated with IL-2. 1. Introduction Human NK cells are a specialized heterogeneous population of lymphocytes of the innate immune system involved in immunosurveillance and contributing to host antimicrobial and antitumor defense reactions. Tese cells are able to lyse target cells spontaneously without presensitization or MHC restriction [1–3]. An equally important function of NK cells is their capacity to produce large quantities of cytokines, such as IFN-, and chemokines upon activation [1, 2, 4]. Moreover, NK cells also act as regulatory cells in the immune system, infuencing other cells and responses and acting as a link between the adaptive and innate immune response. In this way, NK cells actively eliminate susceptible targets by recruit- ing and amplifying the infammatory response through mul- tiple mechanisms. On the other hand, development, survival, proliferation, and efectors functions of NK cells are critically dependent on cytokines, such as IFN-, IL-2, IL-15, and IL- 18 secreted by other cells of the immune system [5]. Of these cytokines, IL-2 is a pluripotent cytokine that can activate NK cells [6, 7], promote their migration within target tissues [8], and increase the secretion of cytokines and other small molecules [9]. Upon stimulation with IL-2, NK cells develop a strong cytolytic activity against target cells by increasing the number and size of cytoplasmic granules [10], augmenting the expression of efector molecules [11], and altering the surface expression of receptors [12]. Moreover, it has been described that IL-2 has the potential to restore the cytotox- icity and granular content of exhausted NK cells [13]. In this context, IL-2 has been used as an immunotherapeutic agent to promote NK cell antitumor activity [14–18]. In fact, early phases of in vivo IL-2 use showed that the antitumor response Hindawi Publishing Corporation Mediators of Inflammation Volume 2016, Article ID 9605253, 10 pages http://dx.doi.org/10.1155/2016/9605253