Salazar K.D.,National Center for Environmental Assessment |
Copeland C.B.,Cardiopulmonary and Immunotoxicology Branch |
Wood C.E.,Carcinogenesis Branch |
Schmid J.E.,Research Cores Unit |
And 2 more authors.
Journal of Immunotoxicology | Year: 2013
The prevalence of anti-nuclear antibodies (ANA) and self-reported systemic autoimmune diseases were increased in residents of Libby, MT, as was the incidence of ANA in Lewis rats exposed to Libby amphibole (LA) asbestos. However, rats induced to develop rheumatoid arthritis (RA) did not develop autoantibodies associated with RA, nor was RA exacerbated by LA exposure, suggesting that increased ANA expression might be related to some other autoimmune process. Libby residents self-reported increased numbers of physician-diagnosed cases of systemic lupus erythematosus (SLE). Thus, the goal of this study was to determine if the increased incidence of ANA in Lewis rats exposed to LA is related to the development of SLE-like disease. Female Lewis rats were intratracheally instilled bi-weekly for 13 weeks with total doses of 0.15, 0.5, 1.5, or 5.0 mg of LA or 0.5 or 1.5 mg of a positive control fiber, amosite. ANA incidence was significantly increased in all asbestos dose groups, although no dose response was observed. The occurrence of proteinuria was increased in LA 0.5, LA 5.0, and amosite 0.5 dose groups; however, the microscopic appearance of the kidneys was normal, no binding of autoimmune complexes to glomerular surfaces was observed, and antibodies to double-stranded DNA were not elevated. Therefore, an increased prevalence of ANA in rats exposed to asbestos does not appear to correlate with disease markers typically observed in SLE. Analysis of ANA specificity for extractable nuclear antigens (ENA) determined that 98% of ENA+ samples were specific for the Jo-1 antigen. Autoantibodies to Jo-1 have been reported in patients with interstitial lung disease, suggesting that autoantibodies to Jo-1 may be a biomarker for asbestos-related pulmonary disease. © 2013 Informa Healthcare USA, Inc.
Park K.-S.,Cancer Cell and Molecular Biology Branch |
Park K.-S.,Kyung Hee University |
Kim D.-S.,Cancer Cell and Molecular Biology Branch |
Ko C.,Cancer Cell and Molecular Biology Branch |
And 2 more authors.
Frontiers in Bioscience - Elite | Year: 2011
Increased levels of transglutaminase 2 (TGase 2) expression have been reported in many inflammatory diseases, as well as in drug resistant cancer cells. Previous reports have shown that TGase 2 is capable of inducing nuclear factor-kappaB (NF-kappaB) activation via depletion of inhibitor of kappaB (I-kappaB)α through polymerization in the absence of I-kappaBalpha kinase activation. This raises the question of whether increased expression of TGase 2 can extend NF-kappaB activation mediated by a canonical activation pathway. In the TGase 2-inducible EcR23/TG cell line, TGase 2 over-expression resulted in sustained activation of NF-κB in the presence of TNF-alpha, for up to 24 hrs, while in the absence of TGase 2 induction, NF-kappaB activity was restored to basal levels within 6 hrs of TNF-alpha treatment. In mice injected with an adenovirus vector expressing TGase 2, NF-kappaB was constitutively activated for up to 5 days, whereas Adeno/GFP-injected mice exhibited attenuated activation of NF-kappaB in response to TNF-α stress. Thus, the presence of increased levels of TGase 2 may exacerbate NF-κB activation in inflammatory states.
Rome Paek A.,Carcinogenesis Branch |
Kim S.H.,Carcinogenesis Branch |
Kim S.S.,Carcinogenesis Branch |
Kim K.T.,Research Institute National Cancer Center |
You H.J.,Carcinogenesis Branch
Experimental and Molecular Medicine | Year: 2010
Expression of zinc-finger protein 143 (ZNF143), a human homolog of the Xenopus transcriptional activator protein Staf, is induced by various DNA-damaging agents including etoposide, doxorubicin, and γ- irradiation. ZNF143 binds to cisplatin-modified DNA, and its levels are increased in cancer cells that are resistant to anticancer drugs, including cisplatin, suggesting that it plays a role in carcinogenesis and cancer cell survival. However, the mechanism of ZNF143 induction in cancer cells remains unclear. Both insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) have been reported to be overexpressed in cancer cells and to be related to anticancer drug resistance, but the identity of the relevant signaling mediators is still being investigated. In the present study, we observed that IGF-1 was able to induce ZNF143 expression in HCT116 human colon cancer cells and that wortmannin, an inhibitor of phosphatidylinositide 3-kinase (PI3-kinase), inhibited this induction, as did diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, and monodansylcardavarine (MDC), a receptor internalization inhibitor. Treatment with MDC dedecreased the IGF-1-stimulated generation of reactive oxygen species. Taken together, these data suggest that IGF-1 induces ZNF143 expression in cancer cells via PI3-kinase and reactive oxygen species generation during receptor internalization.