Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes
Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous regulators of thymic apoptosis. Among these, glucocorticoid-induced leucine zipper (GILZ) is strongly upregulated in the thymus. We have previously demonstrated that GILZ decreases Bcl-xL expression, activates caspase...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Journal of Translational Autoimmunity |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589909020300022 |
| _version_ | 1819203620577476608 |
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| author | Isabella Muscari Sabrina Adorisio Anna Marina Liberati Trinh Thi Thuy Tran Van Sung Lorenza Cannarile Emira Ayroldi Carlo Riccardi Domenico V. Delfino |
| author_facet | Isabella Muscari Sabrina Adorisio Anna Marina Liberati Trinh Thi Thuy Tran Van Sung Lorenza Cannarile Emira Ayroldi Carlo Riccardi Domenico V. Delfino |
| author_sort | Isabella Muscari |
| collection | DOAJ |
| description | Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous regulators of thymic apoptosis. Among these, glucocorticoid-induced leucine zipper (GILZ) is strongly upregulated in the thymus. We have previously demonstrated that GILZ decreases Bcl-xL expression, activates caspase-8 and caspase-3, and augments apoptosis in mice thymocytes. To better understand the causal links between glucocorticoids, GILZ, Bcl-xL, caspase-8, and caspase-3, we analyzed the thymocytes of Bcl-xL-overexpressing transgenic mice with or without glucocorticoid stimulation in vitro. Overexpression of Bcl-xL inhibited the glucocorticoid-induced up-regulation of GILZ in murine thymocytes as well as the glucocorticoid-dependent activation of caspase-8 and caspase-3. By contrast, no appreciable change in caspase-9 activation was observed upon Bcl-xL overexpression. Thus, these experiments highlighted a novel thymocyte apoptotic pathway in which Bcl-xL overexpression inhibited the glucocorticoid-induced activation of caspase-8 and caspase-3, but not caspase-9, as well as the accumulation of GILZ protein. These findings, together with our previous results showing that caspase-8 protects GILZ from proteasomal degradation, suggest the presence of a glucocorticoid-induced apoptosis self-amplification loop in which GILZ decreases Bcl-xL expression with a subsequent activation of caspase-8 and caspase-3; caspase-8 activation then enhances the stability and accumulation of GILZ and ensures the unimpeded and irreversible progression of apoptosis. By contrast, inappropriate increases in Bcl-xL levels could have catastrophic effects on thymic apoptosis as it would shut down caspase-8/3 activation, diminish the expression of GILZ, and impair the fine control necessary for thymic generation of a healthy immune repertoire. |
| first_indexed | 2024-12-23T04:22:49Z |
| format | Article |
| id | doaj.art-6a3beb53350a497ebf1589bae02a3664 |
| institution | Directory Open Access Journal |
| issn | 2589-9090 |
| language | English |
| last_indexed | 2024-12-23T04:22:49Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Translational Autoimmunity |
| spelling | doaj.art-6a3beb53350a497ebf1589bae02a36642022-12-21T18:00:12ZengElsevierJournal of Translational Autoimmunity2589-90902020-01-013100035Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytesIsabella Muscari0Sabrina Adorisio1Anna Marina Liberati2Trinh Thi Thuy3Tran Van Sung4Lorenza Cannarile5Emira Ayroldi6Carlo Riccardi7Domenico V. Delfino8Department of Medicine, University of Perugia, Santa Maria Hospital, Terni, ItalyFoligno Nursing School, Department of Medicine, University of Perugia, Foligno (PG), ItalyDepartment of Medicine, University of Perugia, Santa Maria Hospital, Terni, ItalyInstitute of Chemistry, Vietnam Academy of Science and Technology, Ha Noi, Viet NamInstitute of Chemistry, Vietnam Academy of Science and Technology, Ha Noi, Viet NamSection of Pharmacology, Department of Medicine, University of Perugia, Perugia, ItalySection of Pharmacology, Department of Medicine, University of Perugia, Perugia, ItalySection of Pharmacology, Department of Medicine, University of Perugia, Perugia, ItalyFoligno Nursing School, Department of Medicine, University of Perugia, Foligno (PG), Italy; Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy; Corresponding author. Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy.Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous regulators of thymic apoptosis. Among these, glucocorticoid-induced leucine zipper (GILZ) is strongly upregulated in the thymus. We have previously demonstrated that GILZ decreases Bcl-xL expression, activates caspase-8 and caspase-3, and augments apoptosis in mice thymocytes. To better understand the causal links between glucocorticoids, GILZ, Bcl-xL, caspase-8, and caspase-3, we analyzed the thymocytes of Bcl-xL-overexpressing transgenic mice with or without glucocorticoid stimulation in vitro. Overexpression of Bcl-xL inhibited the glucocorticoid-induced up-regulation of GILZ in murine thymocytes as well as the glucocorticoid-dependent activation of caspase-8 and caspase-3. By contrast, no appreciable change in caspase-9 activation was observed upon Bcl-xL overexpression. Thus, these experiments highlighted a novel thymocyte apoptotic pathway in which Bcl-xL overexpression inhibited the glucocorticoid-induced activation of caspase-8 and caspase-3, but not caspase-9, as well as the accumulation of GILZ protein. These findings, together with our previous results showing that caspase-8 protects GILZ from proteasomal degradation, suggest the presence of a glucocorticoid-induced apoptosis self-amplification loop in which GILZ decreases Bcl-xL expression with a subsequent activation of caspase-8 and caspase-3; caspase-8 activation then enhances the stability and accumulation of GILZ and ensures the unimpeded and irreversible progression of apoptosis. By contrast, inappropriate increases in Bcl-xL levels could have catastrophic effects on thymic apoptosis as it would shut down caspase-8/3 activation, diminish the expression of GILZ, and impair the fine control necessary for thymic generation of a healthy immune repertoire.http://www.sciencedirect.com/science/article/pii/S2589909020300022Bcl-xLGlucocorticoidsCaspase-8Caspase-3GILZThymocytes |
| spellingShingle | Isabella Muscari Sabrina Adorisio Anna Marina Liberati Trinh Thi Thuy Tran Van Sung Lorenza Cannarile Emira Ayroldi Carlo Riccardi Domenico V. Delfino Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes Journal of Translational Autoimmunity Bcl-xL Glucocorticoids Caspase-8 Caspase-3 GILZ Thymocytes |
| title | Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes |
| title_full | Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes |
| title_fullStr | Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes |
| title_full_unstemmed | Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes |
| title_short | Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes |
| title_sort | bcl xl overexpression decreases gilz levels and inhibits glucocorticoid induced activation of caspase 8 and caspase 3 in mouse thymocytes |
| topic | Bcl-xL Glucocorticoids Caspase-8 Caspase-3 GILZ Thymocytes |
| url | http://www.sciencedirect.com/science/article/pii/S2589909020300022 |
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