The major source of thimerosal (ethyl mercury thiosalicylate)
. Thimerosal and not thiosalcylic acid (nonmercury component of thimerosal), in a concentration-dependent manner, induced apoptosis in T cells as determined by TUNEL and propidium iodide assays, suggesting a role of mercury in T cell apoptosis. Apoptosis was associated with depolarization of mitochondrial membrane, release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria, and activation of caspase-9 and caspase-3, but not of caspase-8. In addition, thimerosal in a concentrationdependent manner inhibited the expression of XIAP, cIAP-1 but did not influence cIAP-2 expression. Furthermore, thimerosal enhanced intracellular reactive oxygen species and reduced intracellular glutathione (GSH). Finally, exogenous glutathione protected T cells from thimerosal-induced apoptosis by upregulation of XIAP and cIAP1 and by inhibiting activation of both caspase-9 and caspase-3. These data suggest that thimerosal induces apoptosis in T cells via mitochondrial pathway by inducing oxidative stress and depletion of GSH.
In human aging, lymphocytes display increased sensitivity to tumor necrosis factor-a (TNF-a)-induced apoptosis. TNF-a induces both survival and apoptotic signals. The survival signal is mediated by the activation of NF-jB. Although a role of certain proapoptotic molecules in aging has been reported, a role of altered NF-jB signaling pathway has not been explored in detail. In this study, we have compared TNF-ainduced activation of NF-jB, phosphorylation of IjBa, and the expression of IKKb between lymphocytes from young and aged humans. Furthermore, we have explored a role of IKKb in increased susceptibility of lymphocytes from aged humans to TNF-a-induced apoptosis. Lymphocytes from aged humans displayed decreased activation of NF-jB, reduced phosphorylation of IjBa, and decreased expression of IKKb. In addition, overexpression of IKKb in lymphocytes from aged humans normalized TNF-a-induced apoptosis to the level of young subjects. These data suggest a deficiency of NF-jB signaling pathway and a role of IKKb, at least in part, for increased sensitivity of lymphocytes from aged humans to TNF-a-induced apoptosis.
Increased spontaneous as well as TNF-a-induced and CD95-mediated apoptosis were observed in CD4+ and CD8+ T cells from the cord blood of a patient with Turner's syndrome as compared to normal cord blood. Increased apoptosis was associated with an increased expression of TNFR-1, TNFR-2, and CD95L and decreased expression of cIAP1 and FLIP L . No significant difference was observed in the expression of Bcl-2 family members (Bcl-2, Bax) between Turner's syndrome cord blood and normal cord blood lymphocytes. This study demonstrates that increased apoptosis of T-cell subsets in Turner's syndrome occurs via the death receptor pathway and may play a role in the pathogenesis of immunological defects associated with Turner's syndrome.
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