Tributyltin-induced effects on MAP kinases p38 and p44/42 in human natural killer cells

Abstract

NK cells form a class of lymphocytes that are able to kill tumor cells, virally infected cells and antibody-coated cells without prior sensitization. Tributyltin (TBT) is a toxic chemical that was used in large scale in wood preservation, marine antifouling paints, and slime control in paper mills. TBT has been detected in human foods such as dairy products, meat and fish and detectable levels have been found in human blood. The role of TBT in immunosuppression has been reported and its specific inhibition of the human NK-cell cytotoxic function has also been described. The current studies examined the role of mitogen-activated protein kinases (MAPKs) p38 and p44/42 during TBT-induced inhibition of NK cytotoxic function. Continuous in vitro exposure to 300 nM TBT for 1 h decreased the NK cell cytotoxic function with concomitant increases in phosphorylated forms of both p38 and p44/42 but not the total levels of either of these enzymes. Similar results were obtained with 500 nM TBT treatment. A 1 h exposure to 300 nM TBT followed by 24 h in TBT-free media resulted in a further decrease in the cytotoxic function with an accompanying increase in the phosphorylated forms of p38 and p44/42 MAPKs as compared to controls (approximately 50%). However, after 48 h in TBT-free media, the phosphorylation levels of both p44/42 and p38 MAPKs decreased by about 50 and 30%, respectively. NK cell cytotoxic function also continued to decrease with time in TBT-free media. A 24 h exposure to 200 nM TBT decreased cytotoxic function of NK cells (>90%) but produced donor-dependent effects on the phosphorylated p38 and p44/42 MAPK levels. These data indicated that in vitro exposures to TBT induced changes in the phosphorylation (activation) states of p38 and p44/42 but not in their overall levels of expression in human NK cells.