Vanadium-induced Nuclear Factor of Activated T Cells Activation through Hydrogen Peroxide

Chuanshu Huang, Min Ding, Jingxia Li, Stephen S. Leonard, Yongyut Rojanasakul, Vincent Castranova, Val Vallyathan, Gong Ju, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

The present study investigated the role of reactive oxygen species (ROS) in activation of nuclear factor of activated T cells (NFAT), a pivotal transcription factor responsible for regulation of cytokines, by vanadium in mouse embryo fibroblast PW cells or mouse epidermal Cl 41 cells. Exposure of cells to vanadium led to the transactivation of NFAT in a time- and dose-dependent manner. Scavenging of vanadium-induced H2O 2 with N-acety-L-cyteine (a general antioxidant) or catalase (a specific H2O2 inhibitor) or the chelation of vanadate with deferoxamine, resulted in inhibition of NFAT activation. In contrast, an increase in H2O2 generation by the addition of superoxide dismutase or NADPH enhanced vanadium-induced NFAT activation. This vanadate-mediated H2O2 generation was verified by both electron spin resonance and fluorescence staining assay. These results demonstrate that H2O2 plays an important role in vanadium-induced NFAT transactivation in two different cell types. Furthermore, pretreatment of cells with nifedipine, a calcium channel blocker, inhibited vanadium-induced NFAT activation, whereas A23187 and ionomycin, two calcium ionophores, had synergistic effects with vanadium for NFAT induction. Incubation of cells with cyclosporin A (CsA), a pharmacological inhibitor of the phosphatase calcineurin, blocked vanadium-induced NFAT activation. All data show that vanadium induces NFAT activation not only through a calcium-dependent and CsA-sensitive pathway but also involved H2O2 generation, suggesting that H2O2 may be involved in activation of calcium-calcineurin pathways for NFAT activation caused by vanadium exposure.

Original languageEnglish
Pages (from-to)22397-22403
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number25
DOIs
StatePublished - Jun 22 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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