| Cathepsin-dependent apoptosis triggered by supraoptimal activation of T lymphocytes: a possible mechanism of high dose tolerance. | |
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MedLine Citation:
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PMID: 15100281 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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High doses of Ag can paradoxically suppress immune responses in vivo. This Ag-specific unresponsiveness (termed high dose tolerance) involves extrathymic mechanisms in mature T lymphocytes. To investigate these mechanisms, we used the in vitro model of PBL activated with anti-CD3 or PHA. In these conditions, increasing mitogen concentrations resulted in a reduction of the proliferative response, associated with an increased percentage of apoptotic cells. Apoptosis did not require prior exposure to IL-2, it was not the consequence of CD178/CD95 or TNF/TNFR interactions, and was therefore clearly distinct from activation-induced cell death. Although the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) decreased DNA fragmentation, cytochrome c release and caspase-9 and caspase-3 activation were not implicated, suggesting that this apoptosis did not primarily involve the intrinsic mitochondrial pathway. E64d, a cysteine protease inhibitor, as well as specific inhibitors of cathepsin B and cathepsin L conferred protection. We further demonstrated that cathepsin B and cathepsin L were released from the lysosomes and catalytically active in the cytosol. Release of cathepsin B and cathepsin L was the consequence of lysosomal membrane permeabilization without complete disruption of the cytosol-lysosome pH gradient. These results demonstrate a role for cathepsins in supraoptimal activation-induced apoptosis in vitro and suggest their possible participation in high dose tolerance in vivo. |
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Authors:
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Marie-Cécile Michallet; Frédéric Saltel; Monique Flacher; Jean-Pierre Revillard; Laurent Genestier |
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: 172 ISSN: 0022-1767 ISO Abbreviation: J. Immunol. Publication Date: 2004 May |
Date Detail:
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Created Date: 2004-04-21 Completed Date: 2004-08-17 Revised Date: 2009-11-19 |
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: 5405-14 Citation Subset: AIM; IM |
Affiliation:
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Laboratoire d'Immunopharmacologie, Institut National de la Santé et de la Recherche Médicale Unité 503, Centre d'Etudes et de Recherche en Virologie et Immunologie, Lyon, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Chloromethyl Ketones
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pharmacology Antigens, CD28 / pharmacology Apoptosis / immunology* Caspases / antagonists & inhibitors Catalysis Cathepsin B / antagonists & inhibitors, physiology*, secretion Cathepsin L Cathepsins / antagonists & inhibitors, physiology*, secretion Cell Death / immunology Cell Differentiation / immunology Cells, Cultured Cysteine Endopeptidases Cysteine Proteinase Inhibitors / pharmacology Cytochromes c / secretion Cytosol / enzymology, immunology, secretion DNA Fragmentation / drug effects, immunology Dose-Response Relationship, Immunologic G1 Phase / immunology Humans Intracellular Membranes / enzymology, immunology Lymphocyte Activation / immunology* Lysosomes / enzymology Muromonab-CD3 / pharmacology Permeability S Phase / immunology T-Lymphocytes / cytology, enzymology*, immunology*, secretion Tetradecanoylphorbol Acetate / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Amino Acid Chloromethyl Ketones; 0/Antigens, CD28; 0/Cysteine Proteinase Inhibitors; 0/Muromonab-CD3; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; 16561-29-8/Tetradecanoylphorbol Acetate; 9007-43-6/Cytochromes c; EC 3.4.-/Cathepsins; EC 3.4.22.-/Caspases; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.1/Cathepsin B; EC 3.4.22.15/CTSL1 protein, human; EC 3.4.22.15/Cathepsin L |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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