Tributyltin (TBT) is a widespread environmental contaminant and there is significant exposure of humans to TBT. Measurable levels of TBT have been found in human blood samples. It appears to increase the risk of cancer and viral infections in exposed individuals. Natural Killer (NK) cells are lymphocytes that are capable of killing tumor cells, virally infected cells and antibody coated cells. NK cells are our primary immune defense against viruses and cancer cells. In past studies, we demonstrated that exposure to TBT produced a decrease in the tumor‐cell killing function of human NK cells. Previous studies also showed that exposure of NK cells to TBT activated mitogen activated protein kinases (MAPKs), p44/42 and p38. MAPKs are known to be critical regulators of the tumor‐destroying function of NK cells, in part, by their capacity to alter the function of the transcription regulator AP‐1. The current study addresses the effect of TBT exposure on the phosphorylation state and overall levels of the AP‐1 components, Fos and jun. Such studies are necessary to determine if the alterations in MAPK activity induced by TBT are potentially altering the function of these transcription regulators. NK cells were exposed to TBT and the levels and/or phosphorylation states of Fos and jun were determined using western blotting. The results showed that there was an increase in the phosphorylation (activation) of jun within 10 min of exposure to TBT. There was also an increase in the overall level of fos within 1 hour exposure to the compound. The results indicated that there were alterations of the components of AP‐1, which would result in increased functional capacity. Altered AP‐1 function could in part explain changes in the expression of several NK proteins that have previously been observed.
Tributyltin (TBT) is a toxic man‐made compound that was used in wood preservation, marine antifouling paints, disinfection of circulating industrial cooling waters and slime control in paper mills. Detectable levels have been found in human blood. Exposure to TBT decreases the tumor‐cell lysing (lytic) function of human natural killer (NK) lymphocytes. In this study we assessed the effects of concentrations of TBT that have been shown to decrease NK lytic function on the phosphorylation states of protein tyrosine kinases (PTKs) (Syk, Zap‐70, Src and Pyk) and phospholipase C gamma (PLCγ) in NK cells. Exposure to 500 nM TBT caused no change in phosphorylation of any of the protein tyrosine kinases. A 60 min exposure of NK cells to 500 nM TBT did not significantly affect the phosphorylation state of PLCγ1 at any of the lengths of exposure. However, total levels of PLCγ were increased by almost 50% after 60 minutes of exposure to 500 nM TBT. Exposure of NK cells to 300 nM TBT for 5–60 min caused no significant changes in the phosphorylation state or total level of any of the PTKs or PLCγ. Exposure of NK cells to 200 nM TBT for 24 h caused no significant changes in the PTK or PLCγ phosphorylation state or total levels. Cells that were exposed to 300 nM TBT for 1h followed by 24h or 48h in TBT‐free media showed a significant increase in the phosphorylated forms of Syk (Tyr525) and Zap‐70 after 24 h in TBT‐free media but not after 48 h. These data indicate that in vitro exposure to TBT, under some conditions, induced changes in PLCγ, Phospho‐syk(Tyr525) and Phospho‐zap70. Supported by NIH grant 2S06GM0809228.
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