title: Increased nuclear thioredoxin-1 potentiates cadmium-induced cytotoxicity.
abstract: Cadmium (Cd) is a widely dispersed environmental agent that causes oxidative toxicity through mechanisms that are sensitive to thioredoxin-1 (Trx1). Trx1 is a cytoplasmic protein that translocates to nuclei during oxidative stress. Recent research shows that interaction of Trx1 with actin plays a critical role in cell survival and that increased nuclear Trx-1 potentiates proinflammatory signaling and death in cell and mouse models. These observations indicate that oxidative toxicity caused by low-dose Cd could involve disruption of actin-Trx1 interaction, nuclear Trx1 translocation, and potentiation of proinflammatory cell death mechanisms. In this study, we investigated the role of nuclei-localized Trx1 in Cd-induced inflammation and cytotoxicity using in vitro and in vivo models. The results show that Cd stimulated nuclear translocation of Trx1 and p65 of NF-κB. Elevation of Trx1 in nuclei in in vitro cells and kidney of transgenic mice potentiated Cd-stimulated NF-κB activation and cell death. Cd-stimulated Trx1 nuclear translocation and NF-κB activation were inhibited by cytochalasin D, an inhibitor of actin polymerization, suggesting that actin regulates Trx1 nuclear translocation and NF-κB activation by Cd. A nuclear-targeted dominant negative form of Trx1 blocked Cd-stimulated NF-κB activation and decreased cell death. Addition of zinc, known to antagonize Cd toxicity by increasing metallothionein, had no effect on Cd-stimulated nuclear translocation of Trx1 and NF-κB activation. Taken together, the results show that nuclear translocation and accumulation of redox-active Trx1 in nuclei play an important role in Cd-induced inflammation and cell death.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Go
authors.forename: Michael
authors.initials: M
authors.lastname: Orr
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002104:Cadmium / Q000633:toxicity*; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000235:genetics; D010084:Oxidation-Reduction; D021381:Protein Transport; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004785:Environmental Pollutants; D016328:NF-kappa B; D019913:Nuclear Localization Signals; C491203:TXN protein, human; D002104:Cadmium; D013879:Thioredoxins; D005978:Glutathione; D003545:Cysteine