Abstract
Acute starvation, which is frequently observed in clinical practice, sometimes augments the cytolytic activity of natural killer cells against neoplastic cells. In this study, we investigated the molecular mechanisms underlying the enhancement of natural killer cell function by fasting in mice. The total number of liver resident natural killer cells in a unit weight of liver tissue obtained from C57BL/6J mice did not change after a 3-day fast, while the proportions of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)+ and CD69+ natural killer cells were significantly elevated (n = 7, p <0.01), as determined by flow cytometric analysis. Furthermore, we found that TRAIL− natural killer cells that were adoptively transferred into Rag-2−/− γ chain−/− mice could convert into TRAIL+ natural killer cells in fasted mice at a higher proportion than in fed mice. Liver natural killer cells also showed high TRAIL-mediated antitumor function in response to 3-day fasting. Since these fasted mice highly expressed heat shock protein 70 (n = 7, p <0.05) in liver tissues, as determined by western blot, the role of this protein in natural killer cell activation was investigated. Treatment of liver lymphocytes with 50 µg/mL of recombinant heat shock protein 70 led to the upregulation of both TRAIL and CD69 in liver natural killer cells (n = 6, p <0.05). In addition, HSP70 neutralization by intraperitoneally injecting an anti- heat shock protein 70 monoclonal antibody into mice prior to fasting led to the downregulation of TRAIL expression (n = 6, p <0.05). These findings indicate that acute fasting enhances TRAIL-mediated liver natural killer cell activity against neoplastic cells through upregulation of heat shock protein 70.
Highlights
Natural killer (NK) cells, the front-line defense for the immune system, do not require priming to exert their effector function on neoplastic cells, modified cells, and invading infectious microbes [1,2,3]
We hypothesized that acute starvation may lead to the enhancement of NK cell activity against neoplastic cells by inducing the expression of HSP70. We show that both the proportion of tumor necrosis factor– related apoptosis-inducing ligand (TRAIL)+ NK cells and the expression of HSP70 were significantly elevated in the liver of fasted mice
The proportion of TRAIL+ and CD69+ NK cells increased in mouse livers in response to starvation The phenotypic characteristics of NK cells in mice that had been fasted for 1–3 days were examined by flow cytometry
Summary
Natural killer (NK) cells, the front-line defense for the immune system, do not require priming to exert their effector function on neoplastic cells, modified cells, and invading infectious microbes [1,2,3]. It has been demonstrated that acute starvation, which is frequently observed in clinical practice, sometimes augments the cytolytic activity of NK cells against neoplastic cells [4], the molecular mechanisms underlying this phenomenon remain unclear. Few studies have addressed the question of whether such augmentation of NK cell activity by nutritional alteration is of practical benefit. One is the direct release of cytolytic granules containing perforin, granzymes, and granulysin via the granule exocytosis pathway [1,2]. Another mechanism is mediated by death-inducing ligands such as Fas ligand (FasL) and TRAIL [2,6,8]
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