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. 2014 Apr;69:58-66.
doi: 10.1016/j.freeradbiomed.2014.01.005. Epub 2014 Jan 15.

Significance of the Rapid Increase in GSH Levels in the Protective Response to Cadmium Exposure Through Phosphorylated Nrf2 Signaling in Jurkat T-cells

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Significance of the Rapid Increase in GSH Levels in the Protective Response to Cadmium Exposure Through Phosphorylated Nrf2 Signaling in Jurkat T-cells

Yuki Ogasawara et al. Free Radic Biol Med. .

Abstract

Although cadmium (Cd) is a redox system disruptor, the systematic defensive responses to Cd-induced oxidative stress remain unclear. In this study, we initially determined that when human T-cell-derived Jurkat cells were exposed to a low concentration of Cd, the glutathione (GSH) concentration rapidly increased via the transient nuclear accumulation of the transcription factor Nrf2. Therefore, we hypothesized that this increase in the GSH levels was a significant event that occurred in response to the Cd toxicity in the Jurkat T-cells. To test this hypothesis, the expression of Nrf2 in the cells was silenced using siRNA transfection. These restricted expression conditions demonstrated that the sensitivity of the Jurkat T-cells to Cd toxicity was significantly higher in the knockdown cells. Whereas we could not find differences in the metallothionein (MT) expression responses, accumulation of Nrf2 in the nuclei and the GSH increase after Cd exposure were clearly suppressed in the Nrf2 knockdown cells. These findings strongly suggest that the Cd-induced activation of GSH synthesis is initiated as an acute response for Cd detoxification. Furthermore, the Cd remaining in the Jurkat T-cells did not cause a significant inhibition of cell growth after the rapid and transient increase in the GSH concentration returned to its basal level. Additionally, we found that MT expression induced by Cd occurred much later, with the expression seen at least 12h or more after the Nrf2-dependent immediate responses were almost completed. These results indicate that the rapid increase in GSH is an essential defensive response, with the subsequent induction of MT potentially chelating the Cd retained in the cell, thereby leading to continued suppression of Cd toxicity.

Keywords: Cadmium; Detoxification; Free radicals; Glutathione; Jurkat T-cell; Leukocyte; Metallothionein; Nrf2.

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