Cyclosporin 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 through apoptosis takes place. Two immunosuppressants, cyclosporin A (CsA) and FK506, have been demonstrated to inhibit activation-induced cell 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 with thyroid hormone (T3), the causative agent of metamorphosis. It is surprising that this T3-induced apoptosis was found to be inhibited only by CsA but not by FK506, whereas both immunosuppressants block activation-induced apoptosis in T cells. Since T3 exerts its effect primarily by regulating gene transcription through direct binding to nuclear thyroid hormone receptors, our results strongly suggest that except for their similarity in the T cell receptor-mediated signal transduction process, CsA, but not FK506, also blocks another yet-unidentified step during the induction of apoptosis. The identification of this novel function of CsA may provide an important clue toward the understanding of the mechanism of apoptosis and helps in designing better clinical applications of the immunosuppressants.
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Laboratory of Molecular Embryology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Shi
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Shi
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YB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D053938:DNA Fragmentation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology; D009707:Nucleosomes; D016559:Tacrolimus / Q000494:pharmacology*; D014284:Triiodothyronine / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014982:Xenopus laevis
D007166:Immunosuppressive Agents; D009707:Nucleosomes; D014284:Triiodothyronine; D016572:Cyclosporine; D016559:Tacrolimus