ABSTRACT
The potent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces thymus atrophy in experimental animals. However, its mechanism of action is not fully understood. To gain insight into its immunosuppressive effect, Balb/c mice were intraperitoneally injected with TCDD (30 microg/kg body weight) and genes regulated by TCDD were identified using cDNA arrays [Park and Lee (2002)]. One of the regulated genes was that for plasma glutathione peroxidase (pGPx). Upon TCDD injection, pGPx mRNA levels in the thymus increased, in parallel with increases in GPx activity and the frequency of anti-human pGPx antibody-reactive cells. pGPX mRNA levels were also moderately up-regulated in the testis and spleen. This is the first report that a particular isotype of the glutathione peroxidase family is regulated by TCDD at both mRNA and protein levels. pGPx is expressed in various tissues in contact with body fluids, and detoxifies hydrogen peroxides and lipid hydroperoxides. It will be of interest to assess the role of pGPx in TCDD-induced thymic atrophy.
Subject(s)
Environmental Pollutants/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Glutathione Peroxidase/metabolism , Plasma/enzymology , Polychlorinated Dibenzodioxins/pharmacology , Thymus Gland , Animals , Atrophy/chemically induced , Cell Line , Gene Expression Profiling , Glutathione Peroxidase/genetics , Humans , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Mice , Mice, Inbred BALB C , Oligonucleotide Array Sequence Analysis , RNA, Messenger/metabolism , Thymus Gland/drug effects , Thymus Gland/enzymology , Thymus Gland/pathologyABSTRACT
Although the potent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well known for its immunosuppressive activity, the mechanisms of its action have been difficult to elucidate, partly because of its inability of exerting its effects in vitro. We previously reported that insulin-like growth factor-binding protein-6 (IGFBP-6) expression in the thymus was increased by TCDD treatment of mice and that the TCDD-up-regulation of the IGFBP-6 gene was also observed with EL-4 mouse thymoma cells. In the present study, we examined the effects of IGFBP-6 on the TCDD-mediated cytotoxicity in EL-4 cells. By stably expressing IGFBP-6 sense or anti-sense mRNA in the EL-4 line of mouse thymoma cells, it was possible to isolate clones in which IGFBP-6 expression was increased or decreased. Clones expressing IGFBP-6 sense mRNA displayed increased sensitivity to cytotoxicity mediated by TCDD, whereas clones expressing IGFBP-6 anti-sense mRNA displayed reduced sensitivity. TCDD-induced DNA fragmentation was less pronounced in clones expressing IGFBP-6 anti-sense mRNA than clones expressing IGFBP-6 sense mRNA or the empty vector. Caspase 3 was activated by TCDD and anti-sense IGFBP-6 expression reduced its activity. Interestingly, the effects of TCDD were exerted without aromatic hydrocarbon (Ah) receptor (AhR). Taken together, the results have shown that IGFBP-6 mediates the immunotoxic effects of TCDD in EL-4 cells in an AhR-independent pathway.
