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Glucocorticoids activate a suicide program in mature T lymphocytes: protective action of interleukin-2
1Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
Abstract:
Viability of T cell blasts obtained by concanavalin A stimulation of mouse spleen cells markedly decreases when these cells are exposed to glucocorticoid hormones in the absence of interleukin-2. The mechanism underlying the lysis of the mature lymphocytes seems to correspond to the apoptotic type of cell death inasmuch as an early degradation of DNA into oligonucleosome-length fragments is observed. Moreover, glucocorticoid-induced DNA fragmentation is delayed in the presence of an inhibitor of protein synthesis. Induction of the cell death program by glucocorticoids is most likely mediated through the interaction with a specific glucocorticoid receptor as suggested by the structure-activity relationship of the various steroids tested. Interestingly, the presence of a saturating dose of IL-2 during the treatment of concanavalin A blasts with glucocorticoids totally abolished DNA fragmentation and cell lysis.
Insights
Glucocorticoids induce T cell death via apoptosis, but this effect is blocked by interleukin-2. This suggests a critical role for IL-2 in regulating glucocorticoid-induced T cell apoptosis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- T cell blasts are crucial for immune responses.
- Glucocorticoids are potent immunosuppressants.
- Interleukin-2 (IL-2) is a key T cell growth factor.
Purpose of the Study:
- To investigate the mechanism of T cell death induced by glucocorticoids.
- To determine the role of interleukin-2 in glucocorticoid-mediated T cell apoptosis.
Main Methods:
- Stimulation of mouse spleen cells with concanavalin A to generate T cell blasts.
- Exposure of T cell blasts to glucocorticoids with and without interleukin-2.
- Assessment of cell viability and DNA fragmentation (DNA laddering).
- Evaluation of the effect of protein synthesis inhibitors on glucocorticoid-induced cell death.
Main Results:
- Glucocorticoids significantly reduced T cell blast viability in the absence of IL-2.
- Glucocorticoid treatment induced DNA fragmentation characteristic of apoptosis.
- Inhibition of protein synthesis delayed glucocorticoid-induced DNA fragmentation.
- Specific glucocorticoid receptor interactions were implicated in the cell death pathway.
- IL-2 completely prevented DNA fragmentation and cell lysis caused by glucocorticoids.
Conclusions:
- Glucocorticoids trigger an apoptotic cell death program in T cell blasts.
- This program is dependent on protein synthesis and mediated by glucocorticoid receptors.
- Interleukin-2 plays a critical protective role, completely inhibiting glucocorticoid-induced T cell apoptosis.