Carbamate pesticide-induced apoptosis and necrosis in human natural killer cells.

We previously found that ziram, a carbamate fungicide, significantly induced apoptosis and necrosis in human NK-92MI, a natural killer cell line. To investigate whether other carbamate pesticides also induce apoptosis and necrosis in human natural killer cell, we conducted further experiments with NK-92CI, a human natural killer cell line using a more sensitive assay. NK-92CI cells were treated with ziram, thiram, maneb or carbaryl at 0.031-40 microM for 2-24 h in the present study. Apoptosis and necrosis were determined by FITC-Annexin-V/PI staining. To explore the mechanism of apoptosis, intracellular levels of active caspases 3 and mitochondrial cytochrome-c release were determined by flow cytometry. We found that ziram and thiram also induced apoptosis and necrosis in a time- and dose-dependent manner; however, maneb and carbaryl induced apoptosis and necrosis only at higher doses in NK-92CI cells. The strength of the apoptosis-inducing effect differed among the pesticides, and the order was as follows: thiram > ziram greater than maneb greater than carbaryl. NK-92CI was more sensitive to ziram than NK-92MI. Moreover, ziram and thiram significantly increased the intracellular level of active caspase 3 in NK-92CI and caspase inhibitor significantly inhibited the apoptosis. Ziram and thiram significantly caused mitochondrial cytochrome-c release in NK-92CI. These findings indicate that carbamate pesticides can induce apoptosis in natural killer cells, and the apoptosis is mediated by both the caspase-cascade and mitochondrial cytochrome-c pathways.