Abstract
Multi walled carbon nanotubes (MWCNTs) are one of the most intensively explored nanomaterials because of their unique physical and chemical properties. Due to the widespread use of MWCNTs, it is important to investigate their effects on human health. The precise mechanism of MWCNT toxicity has not been fully elucidated. The present study was designed to examine the mechanisms of MWCNT toxicity toward human promyelocytic leukemia HL-60 cells. First, we found that MWCNTs decreased the viability of neutrophil-like differentiated HL-60 cells but not undifferentiated HL-60 cells. Because neutrophil-like differentiated HL-60 cells exhibit enhanced phagocytic activity, the cytotoxicity of MWCNTs is dependent on the intracellularly localized MWCNTs. Next, we revealed that the cytotoxicity of MWCNTs is correlated with the intracellular accumulation of iron that is released from the engulfed MWCNTs in an acidic lysosomal environment. The intracellular accumulation of iron was repressed by treatment with cytochalasin D, a phagocytosis inhibitor. In addition, our results indicated that iron overload enhanced the release of interleukin-8 (IL-8), a chemokine that activates neutrophils, and subsequently elevated intracellular calcium concentration ([Ca2+]i). Finally, we found that the sustained [Ca2+]i elevation resulted in the loss of mitochondrial membrane potential and the increase of caspase-3 activity, thereby inducing apoptotic cell death. These findings suggest that the iron overload caused by engulfed MWCNTs results in the increase of IL-8 production and the elevation of [Ca2+]i, thereby activating the mitochondria-mediated apoptotic pathway.
Highlights
Since the discovery of carbon nanotubes (CNTs) in 1991 by Iijima[1], CNTs have attracted immense attention in the scientific and technological community
We evaluated the cytotoxicity of two types of multi walled carbon nanotubes (MWCNTs) toward HL-60 that differentiated into neutrophil-like cells and undifferentiated cells using the WST-1 assay
As dimethyl sulfoxide (DMSO)-differentiated HL-60 exhibited enhanced phagocytic activity[33], our results suggest that the cytotoxicity of MWCNTs is dependent on the intracellularly localized MWCNTs
Summary
Since the discovery of carbon nanotubes (CNTs) in 1991 by Iijima[1], CNTs have attracted immense attention in the scientific and technological community. It has been reported that short MWCNTs induced more TNF-ɑ production than long MWCNTs in THP-1 macrophages and RAW 264.7 cells[24,25]. These contrasting results can be attributed to the conditions for in vitro analysis and the cell types used for assays[26,27]. In the present study, we investigated MWCNT-induced cytotoxicity and its impact on the mitochondria-mediated apoptotic pathway in human promyelocytic leukemia HL-60 cells that differentiated into neutrophil-like cells. Our data indicated that iron overload caused by MWCNTs triggered the production of IL-8 and the increase of intracellular calcium levels, and these were followed by the activation of the mitochondria-mediated apoptotic pathway
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