Pattern of MAP kinases p44/42 and JNK activation by non-lethal doses of tributyltin in human natural killer cells.

Tributyltin (TBT) has been shown to disrupt the ability of natural killer (NK) cells to destroy tumor targets in vitro even at exposures of 25 nM for 24 h, but cell viability was not significantly impacted. Thus, evaluation of intracellular molecular events that regulate cell viability in TBT exposed NK cells are of interest. It has been suggested that activation of the mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), may promote apoptosis while activation of the MAPK p44/42 may be crucial in mediating anti-apoptotic stimuli. However, it is well established that increases in pro-apoptotic BCL-2 family members, such as Bax, results in cell death. We have set out to study the effects of a range of TBT concentrations on the MAPKs, JNK and p44/42. Additionally, we examined the effects of TBT on the levels of pro-apoptotic proteins Bax and p53 as well as anti-apoptotic protein Bcl-2. The results show that 300-25 nM TBT activated JNK within 10 min. MAPK p44/42 was also activated by 300-50 nM TBT within 10 min. These data show that while 300-200 nM TBT activates p44/42 significantly more than JNK, the pattern of 100-25 nM TBT activation of these MAPKs may be similar. TBT exposure alters neither pro-apoptotic proteins Bax and p53 nor anti-apoptotic protein Bcl-2 levels at any exposure studied. The results suggest that exposure to TBT activated the anti-apoptotic regulatory p44/42 pathway to a greater extent than the pro-apoptotic JNK pathway, which may explain to some extent how NK cell viability is maintained.