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-tetrachloro-dibenzo-p -dioxin (TCDD) all affect the immune system, causing immunosuppression and thymic atrophy. It is still uncertain how and where these compoun ds act to induce thymic atrophy. However, it has been suggested that t hese compounds may have similar actions and targets, i.e., apoptosis o f immature thymocytes for Dex and TCDD and preferential targeting of d ouble-positive cells by Dex and E2. The lck(pr)-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 pr otect against E2- and TCDD-induced thymic atrophy. Our results indicat e that, although the bcl-2 transgenic (TG+) mice were fully protected from atrophy induced by a single dose of Dex, atrophy was still induce d in these mice following treatment with E2 or TCDD. Phenotypic analys is of thymocytes from TG- and TG+ mice also showed distinct consequenc es of atrophy induced by Dex, E2, and TCDD. Finally, since there are a lternative pathways for apoptosis that are bcl-2 independent, both TG- and TG+ thymocytes were examined directly for indications of apoptosi s using the TUNEL assay. After TCDD and E2 treatment there were no det ectable signs of apoptosis in either TG- or TG+ mice even at early tim e points and at elevated dose levels. These results indicate that ther e 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-induc ed thymic atrophy. (C) 1998 Academic Press.