Activation of p44/42 MAPK plays a role in the TBT-induced loss of human natural killer (NK) cell function

Abstract

Natural Killer (NK) cells destroy (lyse) tumor cells, virally infected cells and antibody-coated cells. Previous studies indicated that exposure to the environmental contaminant tributyltin (TBT) decreases the lytic function of NK cells and activates mitogen activated protein kinases (MAPK), including p44/42 (Aluoch and Whalen, 2005). If activation of p44/42 is required for TBT-induced decreases of lytic function, then activation of p44/42 to similar extents by pharmacological agents such as Phorbol 12-myristate 13-acetate (PMA) should mimic to some extent changes induced in NK cells with TBT exposures. NK cells were exposed to PMA concentrations between 0.25 and 10 nM for 10 min, 1 h, and 6 h before determining the lytic function (51Cr release assay) and phosphorylation state of MAPKs (Western blot). A 1 h exposure of NK cells to 5 nM PMA resulted in a loss of lytic function of 47%. Western blot analysis showed that a 1 h exposure to 5 nM PMA caused a 6 fold increase in phospho-p44/42 levels. Previous studies showed a 5 fold increase in phospho-p44/42 in response to a 1 h exposure to 300 nM TBT. Exposure to 300 nM TBT caused about a 40% decrease in lytic function. This study supports the hypothesis that p44/42 activation (as seen with TBT exposures) can cause a loss of NK-cell lytic function.

Activation of p44/42 in human natural killer cells decreases cell-surface protein expression: Relationship to tributyltin-induced alterations of protein expression

“…Stimulation of p44/42 (to an extent similar to what was seen with TBT) (Aluoch and Whalen 2005; Aluoch et al , 2006) was able to decrease NK lytic function in a manner similar to that seen with TBT (Dudimah et al , 2010). …”

“…Exposure of NK cells to this concentration of PMA resulted in a significant loss of the cell-surface proteins CD11a, CD16, CD18, and CD56 (P<0.05) compared to the control. 2.5 nM PMA has previously been shown to activate p44/42 in NK cells by approximately 10 fold (Dudimah et al , 2010). The treatment resulted in expression of CD11a at a level of 30% of that seen in control cells (a 70% loss of CD11a), CD16 expression was 17% of control (83% decrease), CD18 was expressed at 37% of control levels (63% decrease), and CD56 expression was 50% of control.…”

“…The role that activation of p44/42 (versus activation of the other MAPKs) plays in the loss of NK cell lytic function has been previously examined (Dudimah et al , 2010) by selectively stimulating (Chang et al , 2005) the p44/42 MAPK pathway using phorbol 12-myristate 13-acetate (PMA). Stimulation of p44/42 (to an extent similar to what was seen with TBT) (Aluoch and Whalen 2005; Aluoch et al , 2006) was able to decrease NK lytic function in a manner similar to that seen with TBT (Dudimah et al , 2010).…”

Brominated flame retardants, tetrabromobisphenol A and hexabromocyclododecane, activate mitogen-activated protein kinases (MAPKs) in human natural killer cells

“…Decreased expression of cell surface proteins involved in the cytotoxic process was also seen following activation of p44/42 by PMA (Dudimah et al, 2010b). Both TBBPA and HBCD were able to activate p44/42 and we have shown previously that activation of p44/42 decreases NK lytic function (Dudimah et al, 2010a). Thus, activation of this pathway appears to part of the mechanism by which these flame retardants diminish NK function.…”

“…Those studies showed that inhibition of the p44/42 pathway by the MEK inhibitor PD98059 blocked NK cell mediated destruction of tumor cells as well as target stimulation of interferon gamma (IFNγ) synthesis. Additionally, we have previously shown that activation of p44/42 in NK cells by phorbol 12 myristate 13 acetate (PMA) prior to their contact with target cells rendered the NK cell unable to lyse the target cells (Dudimah et al, 2010a). This loss of function was seen within an hour of p44/42 activation (Dudimah, et al, 2010a).…”