CYCLOSPORINE-A BUT NOT FK506 INHIBITS THYROID HORMONE-INDUCED APOPTOSIS IN TADPOLE INTESTINAL EPITHELIUM

Amphibian metamorphosis and mammalian T cell development represent two of the best known systems where developmental programmed cell death t hrough apoptosis takes place. Two immunosuppressants, cyclosporin A (C sA) and FK506, have been demonstrated to inhibit activation-induced ce ll death in immature T cells and T cell hybridomas. In this study, we have established an in vitro system in which isolated primary tadpole intestinal epithelial cells undergo typical apoptosis upon treatment w ith thyroid hormone (T-3), the causative agent of metamorphosis. It is surprising that this T-3-induced apoptosis was found to be inhibited only by CsA but not by FK506, whereas both immunosuppressants block ac tivation-induced apoptosis in T cells. Since T-3 exerts its effect pri marily by regulating gene transcription through direct binding to nucl ear thyroid hormone receptors, our results strongly suggest that excep t for their similarity in the T cell receptor-mediated signal transduc tion process, CsA, but not FK506, also blocks another yet-unidentified step during the induction of apoptosis. The identification of this no vel function of CsA may provide an important clue toward the understan ding of the mechanism of apoptosis and helps in designing better clini cal applications of the immunosuppressants.