Critical role of hydrogen peroxide in the differential susceptibility of Th1 and Th2 cells to tributyltin-induced apoptosis.

ABSTRACT

Tributyltin (TBT), an environmental pollutant, debilitates immune responses via induction of apoptosis in CD4(+) T cells through an undefined mechanism of action. Accumulating evidence indicates that the susceptibility of Th1 and Th2 cells to TBT-induced apoptosis differs. In this study, by using HL-60 cell model, we show that hydrogen peroxide (H(2)O(2)) plays a critical role in TBT-induced apoptosis. Generation of H(2)O(2) induced by TBT resulted in a change in mitochondrial membrane potential that proceed apoptotic pathway where, at least in part, involved activation of caspase-3. We also demonstrated that Th1 clones appear to be more vulnerable to apoptosis induction than Th2 clones following exposure to TBT, which was well correlated with increased H(2)O(2) generation in Th1 clones than Th2 clones. There was an inverse correlation between TBT-induced apoptosis and the basal levels of intracellular GSH, a major cellular antioxidant. Furthermore, the addition of NAC that replenish intracellular GSH levels inhibited generation of H(2)O(2) and apoptosis in Th1 clones. These results suggest that TBT selectively induces apoptosis via generation of H(2)O(2) in Th1 cells because of their low GSH levels, which may contribute to the Th2 predominance induced by TBT.