The role of MEK in TBT‐induced activation of p44/42 in human natural killer cells

Abstract

Natural killer cells are lymphocytes capable of killing tumor cells, virally infected cells and antibody‐coated cells. 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 fish and detectable levels have been found in human blood. Studies have shown that tributyltin (TBT) can significantly reduce the cytotoxic function of the human NK cells with accompanying changes in the phosphorylation (activation) state of the mitogen activated protein kinase (MAPK), p44/42. The current studies are designed to examine the role of MAPK pathway activation in the TBT‐induced loss of NK cytotoxic function, by using MAPK kinase (MEK) inhibitors. MAPK pathway activation was inhibited by compounds that specifically block the activation of MEK. Several MEK inhibitors were examined. There was about a 30% decrease in NK cell cytotoxic function when NK cells were exposed for 1h to the MEK inhibitor, PD98059. Western blot analysis using an antibody to phospo‐p44/42 showed that PD98059 was able to completely block TBT‐induced activation of p44/42. These results indicate that activation of p44/42 pathway is needed for the cytotoxic function of freshly isolated human NK cells and that TBT‐induced activation of p44/42 occurs via the activation of its upstream activator, MEK.