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Programmed T lymphocyte death. Cell activation- and steroid-induced pathways are mutually antagonistic
C M Zacharchuk1, M Merćep, P K Chakraborti
1Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Journal of Immunology (Baltimore, Md. : 1950)
|December 25, 1990
Summary
Cellular activation signals and dexamethasone (Dex) induce T cell death, but activation reduces Dex-induced killing. This study reveals activation does not directly use the glucocorticoid pathway to inhibit Dex-mediated cell death.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Cellular activation and glucocorticoids like dexamethasone (Dex) induce programmed cell death in T cell hybridomas.
- Co-exposure to Dex and activation signals reduces cell death compared to individual stimuli.
- This suggests an antagonistic interaction between these two cell death pathways.
Purpose of the Study:
- To investigate the mechanisms by which cellular activation antagonizes dexamethasone-induced programmed cell death in T cells.
- To determine if cellular activation interferes with the classical glucocorticoid signaling pathway.
Main Methods:
- T cell hybridomas and normal T cell clones were treated with dexamethasone (Dex) and/or activation signals.
- Experiments utilized Cyclosporin A (CsA), RU-486 (glucocorticoid receptor antagonist), and gene transfection with a chloramphenicol acetyltransferase (CAT) reporter construct.
- Glucocorticoid receptor translocation was assessed via cellular fractionation and microscopy.
Main Results:
- Cellular activation significantly reduced Dex-induced T cell death, while Cyclosporin A (CsA) blocked activation-induced death but enhanced Dex-induced killing.
- Activation did not inhibit RU-486 binding or glucocorticoid receptor translocation to the nucleus.
- Reporter gene assays showed activation did not block, and paradoxically increased, Dex-induced gene transcription.
Conclusions:
- Cellular activation does not directly engage the glucocorticoid receptor or its classical signaling pathway to induce programmed cell death.
- The antagonism of Dex-mediated killing by cellular activation occurs downstream of gene transcription initiation.
- Findings suggest alternative antagonistic mechanisms and have implications for thymocyte selection.