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Interleukins modulate glucocorticoid-induced thymocyte apoptosis
G Migliorati1, C Pagliacci, R Moraca
1Institute of Pharmacology, School of Medicine, University of Perugia, Italy.
Abstract:
Glucocorticoid hormones, calcium ionophores and anti-CD3 monoclonal antibodies induce apoptosis in mouse thymocytes. This type of cell death, which is characterized by an extensive DNA fragmentation into oligonucleosomal subunits, occurs in the intrathymic process of negative selection, and is involved in the deletion of autoreactive T-cells during thymic maturation. A number of cytokines are able to modulate apoptosis, and interleukins, including interleukin-1, interleukin-2, and interleukin-4, play a crucial role in thymic maturation and T-cell development. We tested the effects of several cytokines on the glucocorticoid hormone-induced apoptosis of mouse thymocytes in vitro, and demonstrated that interleukin-1 alpha, interleukin-2, and interleukin-4 inhibit the apoptosis induced by dexamethasone, but that interleukin-3 and interleukin-6 exert no noteworthy effect. Dose-response experiments indicated that interleukin-4 is more potent than interleukin-1 alpha and interleukin-2 in inhibiting dexamethasone-induced apoptosis. Furthermore, interleukin-4 fully inhibited the DNA fragmentation induced by the protein kinase-C activator 12-O-tetradecanoylphorbol-13-acetate, but was ineffective against apoptosis induced by the calcium ionophore A23187. These results suggest that interleukins regulate the thymic selection process by acting as modulators of the negative selection process.
Insights
Interleukins 1 alpha, 2, and 4 inhibit glucocorticoid-induced apoptosis in mouse thymocytes, crucial for T-cell development. Interleukin-4 shows the most potent inhibition, highlighting its role in regulating thymic selection.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Apoptosis, or programmed cell death, is vital for T-cell development and deletion of autoreactive cells during thymic maturation.
- Glucocorticoids and calcium ionophores are known inducers of thymocyte apoptosis, a process implicated in negative selection.
Purpose of the Study:
- To investigate the modulatory effects of various cytokines on glucocorticoid-induced apoptosis in mouse thymocytes.
- To determine the relative potency of different interleukins in inhibiting dexamethasone-induced apoptosis.
Main Methods:
- In vitro culture of mouse thymocytes.
- Induction of apoptosis using dexamethasone (a glucocorticoid) and other agents.
- Assessment of apoptosis via DNA fragmentation.
- Dose-response studies with various interleukins.
Main Results:
- Interleukin-1 alpha, interleukin-2, and interleukin-4 significantly inhibited dexamethasone-induced apoptosis.
- Interleukin-4 demonstrated greater potency than interleukin-1 alpha and interleukin-2.
- Interleukin-4 also inhibited apoptosis induced by a protein kinase-C activator but not by a calcium ionophore.
Conclusions:
- Interleukins, particularly interleukin-4, act as crucial modulators of the negative selection process in the thymus.
- These findings suggest a regulatory role for interleukins in controlling T-cell maturation and preventing autoimmunity.