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Fasting enhances TRAIL-mediated liver natural killer cell activity via HSP70 upregulation.

Dang VT, Tanabe K, Tanaka Y, Tokumoto N, Misumi T, Saeki Y, Fujikuni N, Ohdan H - PLoS ONE (2014)

Bottom Line: Liver natural killer cells also showed high TRAIL-mediated antitumor function in response to 3-day fasting.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).These findings indicate that acute fasting enhances TRAIL-mediated liver natural killer cell activity against neoplastic cells through upregulation of heat shock protein 70.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

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.

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Western blot analysis of heat shock protein expression in fasted mouse livers.(A) Heat shock protein (HSP)70, HSP27, and β-actin expression in the livers from fed mice (control) and 3-day-fasted mice (7 mice in each group) was determined by western blot. (B) The bar graph shows the average HSP70/β-actin densities plus standard error of the mean; densities were analyzed using ImageJ software. Statistical analyses were performed using the independent samples T test. *p <0.05.
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pone-0110748-g006: Western blot analysis of heat shock protein expression in fasted mouse livers.(A) Heat shock protein (HSP)70, HSP27, and β-actin expression in the livers from fed mice (control) and 3-day-fasted mice (7 mice in each group) was determined by western blot. (B) The bar graph shows the average HSP70/β-actin densities plus standard error of the mean; densities were analyzed using ImageJ software. Statistical analyses were performed using the independent samples T test. *p <0.05.

Mentions: It has been demonstrated that HSP70 actively released in the extracellular space activates NK cells [18], [22]. Hence, HSPs induced by acute starvation may play a role in TRAIL-mediated antitumor activity. We found that HSP70 expression was significantly higher in 3-day-fasted mouse liver than in fed mouse liver (p <0.05), while HSP27 expression was not changed (Figure 6).


Fasting enhances TRAIL-mediated liver natural killer cell activity via HSP70 upregulation.

Dang VT, Tanabe K, Tanaka Y, Tokumoto N, Misumi T, Saeki Y, Fujikuni N, Ohdan H - PLoS ONE (2014)

Western blot analysis of heat shock protein expression in fasted mouse livers.(A) Heat shock protein (HSP)70, HSP27, and β-actin expression in the livers from fed mice (control) and 3-day-fasted mice (7 mice in each group) was determined by western blot. (B) The bar graph shows the average HSP70/β-actin densities plus standard error of the mean; densities were analyzed using ImageJ software. Statistical analyses were performed using the independent samples T test. *p <0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214715&req=5

pone-0110748-g006: Western blot analysis of heat shock protein expression in fasted mouse livers.(A) Heat shock protein (HSP)70, HSP27, and β-actin expression in the livers from fed mice (control) and 3-day-fasted mice (7 mice in each group) was determined by western blot. (B) The bar graph shows the average HSP70/β-actin densities plus standard error of the mean; densities were analyzed using ImageJ software. Statistical analyses were performed using the independent samples T test. *p <0.05.
Mentions: It has been demonstrated that HSP70 actively released in the extracellular space activates NK cells [18], [22]. Hence, HSPs induced by acute starvation may play a role in TRAIL-mediated antitumor activity. We found that HSP70 expression was significantly higher in 3-day-fasted mouse liver than in fed mouse liver (p <0.05), while HSP27 expression was not changed (Figure 6).

Bottom Line: Liver natural killer cells also showed high TRAIL-mediated antitumor function in response to 3-day fasting.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).These findings indicate that acute fasting enhances TRAIL-mediated liver natural killer cell activity against neoplastic cells through upregulation of heat shock protein 70.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

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.

Show MeSH
Related in: MedlinePlus