Biochemical and kinetic characterization of the glucocorticoid-induced apoptosis of immature CD4(+)CD8(+) thymocytes Journal Article
| Authors: | Ivanov, V. N.; Nikolić-Žugić, J. |
| Article Title: | Biochemical and kinetic characterization of the glucocorticoid-induced apoptosis of immature CD4(+)CD8(+) thymocytes |
| Abstract: | We characterized kinetic and biochemical changes during glucocorticoid (GC)-induced apoptosis of immature CD8+CD4+ double-positive (DP) thymocytes. A GC analog dexamethasone (Dex) induced rapid apoptotic commitment and a transient up-regulation of the NF-κB/RelA-p50-binding activity in DP cells. This required an early activation of proteasome, as judged by the ability of a specific proteasomal inhibitor, lactacystine, to delay apoptosis and to suppress Dex-dependent NF-κB activation. Dex-induced apoptotic commitment was preceded by the rapid (3 h) cleavage of both a typical caspase substrate, poly(ADP-ribose) polymerase (PARP), and of nuclear transcription factors AP-1, NF-κB p50-p50 and NUR-77. By contrast, phorbol myristate acetate (PMA) and/or ionomycin-induced apoptosis had much slower kinetics, were preceded by an early increase of NF-κB/RelA-p50, AP-1 and NUR-77 activities, and were insensitive to proteasome inhibition. Both the transgenic Bcl-2 and zVAD-fmk, an inhibitor of caspases, affected all features of Dex-induced apoptosis in a similar fashion, by inhibiting cell death and PARP cleavage, and by stabilizing AP-1, NF-κB p50-p50 and NUR-77 levels. Furthermore, Bcl-2 prevented Dex-induced RelA-p50 activation. However, a higher gene dosage of the transgenic Bcl-2 was required for protection against Dex, compared to the PMA and/or ionomycin-induced apoptosis. These findings highlight the unique mechanistic features of GC-induced apoptosis. |
| Keywords: | controlled study; nonhuman; cd8 antigen; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; protein bcl 2; apoptosis; proteasome; proteasome endopeptidase complex; protein degradation; animal experiment; protein binding; dexamethasone; immunoglobulin enhancer binding protein; transcription factor rela; caspase inhibitor; caspases; cysteine proteinase inhibitors; mice, inbred c57bl; transcription factors; nf-kappa b; cd4-positive t-lymphocytes; transgene; glucocorticoid; cd4 antigen; gene dosage; up-regulation; multienzyme complexes; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; proto-oncogene proteins c-bcl-2; thymocyte; transgenes; phorbol 13 acetate 12 myristate; tetradecanoylphorbol acetate; ionomycin; transcription factor ap 1; corticosteroids; thymocytes; cysteine endopeptidases; ionophores; acetylcysteine; lactacystin; female; priority journal; article |
| Journal Title: | International Immunology |
| Volume: | 10 |
| Issue: | 12 |
| ISSN: | 0953-8178 |
| Publisher: | Oxford University Press |
| Date Published: | 1998-12-01 |
| Start Page: | 1807 |
| End Page: | 1817 |
| Language: | English |
| PUBMED: | 9885901 |
| PROVIDER: | scopus |
| DOI: | 10.1093/intimm/10.12.1807 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 12 December 2016 -- Source: Scopus |
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