| Cyclosporin A abolishes CD28-mediated resistance to CD95-induced apoptosis via superinduction of caspase-3. | |
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MedLine Citation:
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PMID: 17114439 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Costimulation of T cells via CD28 promotes both proliferation and resistance to apoptosis. In this study, we show that the immunosuppressive drug cyclosporin A (CsA) fully reverses resistance to CD95-mediated cell death after TCR/CD28 costimulation or superagonistic anti-CD28 mAb stimulation of primary rat lymph node T cells. This effect correlated with a pronounced superinduction of caspase-3 on both mRNA and protein levels, whereas its main antagonist, X chromosome-linked inhibitor of apoptosis, was unaffected by inclusion of CsA. Apoptosis triggered by CD95 cross-linking was characterized by robust caspase-3 activation. Furthermore, CsA sensitization to CD95-mediated apoptosis of CD28-activated T cells did not alter mRNA stability of superinduced caspase-3 mRNA, suggesting a transcriptional regulation of the caspase-3 gene. Addition of Ca(2+) ionophores to TCR/CD28 or superagonistic CD28-stimulated cells reduced caspase-3 levels, further supporting a role for Ca(2+)-dependent signaling pathways in negatively regulating caspase-3. Taken together, these findings suggest that CsA promotes sensitivity to CD95-mediated apoptosis in CD28-stimulated T cells by superinduction of the caspase-3 gene via a mechanism involving suppression of the calcineurin pathway. |
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Authors:
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Andreas Kerstan; Nicole Armbruster; Martin Leverkus; Thomas Hünig |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 177 ISSN: 0022-1767 ISO Abbreviation: J. Immunol. Publication Date: 2006 Dec |
Date Detail:
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Created Date: 2006-11-20 Completed Date: 2007-01-16 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 7689-97 Citation Subset: AIM; IM |
Affiliation:
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Institute for Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, CD28 / immunology, metabolism* Antigens, CD95 / immunology, metabolism* Apoptosis / drug effects*, immunology Blotting, Western Calcineurin / drug effects, metabolism Caspase 3 / drug effects, genetics, metabolism Cyclosporine / pharmacology* Immune Tolerance Immunoprecipitation Immunosuppressive Agents / pharmacology* Lymphocyte Activation / drug effects, immunology RNA, Messenger / analysis Rats Rats, Inbred Lew Receptors, Antigen, T-Cell / drug effects, immunology T-Lymphocytes / drug effects*, immunology |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD28; 0/Antigens, CD95; 0/Immunosuppressive Agents; 0/RNA, Messenger; 0/Receptors, Antigen, T-Cell; 59865-13-3/Cyclosporine; EC 3.1.3.16/Calcineurin; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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