Overexpression of the anti-apoptotic oncogene, bcl-2, in the thymus does not prevent thymic atrophy induced by estradiol or 2,3,7, 8-tetrachlorodibenzo-p-dioxin.
Dexamethasone (Dex), estradiol (E2), and 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) all affect the immune system, causing immunosuppression and thymic atrophy. It is still uncertain how and where these compounds act to induce thymic atrophy. However, it has been suggested that these compounds may have similar actions and targets, i.e., apoptosis of immature thymocytes for Dex and TCDD and preferential targeting of double-positive cells by Dex and E2. The lckpr-bcl-2 transgenic mouse has been shown to be protected against Dex-induced thymic atrophy. We used this murine model to determine if bcl-2 expression would also protect against E2- and TCDD-induced thymic atrophy. Our results indicate that, although the bcl-2 transgenic (TG+) mice were fully protected from atrophy induced by a single dose of Dex, atrophy was still induced in these mice following treatment with E2 or TCDD. Phenotypic analysis of thymocytes from TG- and TG+ mice also showed distinct consequences of atrophy induced by Dex, E2, and TCDD. Finally, since there are alternative pathways for apoptosis that are bcl-2 independent, both TG- and TG+ thymocytes were examined directly for indications of apoptosis using the TUNEL assay. After TCDD and E2 treatment there were no detectable signs of apoptosis in either TG- or TG+ mice even at early time points and at elevated dose levels. These results indicate that there are distinct mechanisms for the actions of Dex, E2, and TCDD in the thymus and that apoptosis is not a key mechanism of E2- and TCDD-induced thymic atrophy.
Staples
J E
JE
Health Science Center, State University of New York, Syracuse, New York, 13210, USA.
Fiore
N C
NC
Frazier
D E
DE
Gasiewicz
T A
TA
Silverstone
A E
AE
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001284:Atrophy / Q000139:chemically induced / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002452:Cell Count; D003907:Dexamethasone / Q000633:toxicity; D004958:Estradiol / Q000633:toxicity*; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D013950:Thymus Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D000072317:Polychlorinated Dibenzodioxins; D019253:Proto-Oncogene Proteins c-bcl-2; D004958:Estradiol; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins