Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway

Makani, Samir; Gollapudi, Sastry; Yel, Leman; Chiplunkar, Sujata; Gupta, Sudhir

doi:10.1038/sj.gene.6363854

Cited by 55 publications

(44 citation statements)

References 57 publications

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“…Thus, the toxicity of thimerosal in the body may depend upon the concentrations of metal ions that provide either additive toxicity or protective effects on PI3-kinase signaling. Thimerosal has been reported to activate apoptosis in lymphocytes 62 and in cultured human cortical neurons, 63 consistent with the inhibition of the PI3-kinase signaling pathway.…”

Section: Igf-1 and Dopamine Regulate Methionine Synthase M Waly Et Almentioning

confidence: 71%

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

et al. 2004

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Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)-and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase-and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylationsensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu 2 þ promoted enzyme activity and methylation, while Cu þ , Pb 2 þ , Hg 2 þ and Al 3 þ were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1-and dopamine-stimulated methylation with an IC 50 of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.

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Section: Igf-1 and Dopamine Regulate Methionine Synthase M Waly Et Almentioning

confidence: 71%

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

et al. 2004

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“…A recent in vitro study of Thimerosal immunotoxicity using immortalized Jurkat T cells demonstrated an increase in reactive oxygen species and a decrease in intracellular glutathione with increasing concentrations of Thimerosal (Makani et al, 2002). Thimerosal, but not thiosalacylic acid (the non-mercury component of Thimerosal), induced apoptotic cell death in T cells in a concentration-dependent manner as evidenced by mitochondrial release of cytochrome c, apoptosis activating factor, and activation of caspases 9 and 3.…”

Section: Discussionmentioning

confidence: 98%

Thimerosal Neurotoxicity is Associated with Glutathione Depletion: Protection with Glutathione Precursors

et al. 2005

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“…We envisaged that one such redox alteration may be the induction of cell death by apoptosis. 17,18 To test this idea we used both thimerosal 19 and hydrogen peroxide 20 as pro-apoptotic treatments to induce cell death, and monitored induction of MHC class I dimers by immunoblotting of cell lysates with HC10. Jesthom cells incubated with a range of thimerosal (1-5 lM) and hydrogen peroxide (0Á125-1 mM) concentrations showed significant MHC class I dimer formation (Fig.…”

Section: Hydrogen Peroxide and Thimerosal-induced Cell Death Induces mentioning

confidence: 99%

MHC class I dimer formation by alteration of the cellular redox environment and induction of apoptosis

et al. 2012

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SummaryMany MHC class I molecules contain unpaired cysteine residues in their cytoplasmic tail domains, the function of which remains relatively uncharacterized. Recently, it has been shown that in the small secretory vesicles known as exosomes, fully folded MHC class I dimers can form through a disulphide bond between the cytoplasmic tail domain cysteines, induced by the low levels of glutathione in these extracellular vesicles. Here we address whether similar MHC class I dimers form in whole cells by alteration of the redox environment. Treatment of the HLA-B27-expressing Epstein-Barr virus-transformed B-cell line Jesthom, and the leukaemic T-cell line CEM transfected with HLA-B27 with the strong oxidant diamide, and the apoptosis-inducing and glutathione-depleting agents hydrogen peroxide and thimerosal, induced MHC class I dimers. Furthermore, induction of apoptosis by cross-linking FasR/CD95 on CEM cells with monoclonal antibody CH-11 also induced MHC class I dimers. As with exosomal MHC class I dimers, the formation of these structures on cells is controlled by the cysteine at position 325 in the cytoplasmic tail domain of HLA-B27. Therefore, the redox environment of cells intimately controls induction of MHC class I dimers, the formation of which may provide novel structures for recognition by the immune system.

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Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway

Cited by 55 publications

References 57 publications

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

Thimerosal Neurotoxicity is Associated with Glutathione Depletion: Protection with Glutathione Precursors

MHC class I dimer formation by alteration of the cellular redox environment and induction of apoptosis

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