Document Detail


Molecular mechanisms of sulfasalazine-induced T-cell apoptosis.
MedLine Citation:
PMID:  12381674     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Impaired apoptosis of T-lymphocytes is involved in the development of chronic inflammatory disorders. Previously we have shown that the anti-inflammatory drug sulfasalazine induces apoptosis in a murine T-lymphocyte cell line. The aims of the present study were to expand these observations to human systems and to analyse the molecular basis for sulfasalazine-induced apoptosis. Sulfasalazine induces apoptosis both in Jurkat cells, a human T-leukaemia cell line (ED50 value approximately 1.0 mM), and in primary human peripheral blood T-lymphocytes (ED50 value approximately 0.5 mM). In contrast SW620 colon carcinoma cells or primary human synoviocytes are not affected at these concentrations suggesting a cell type-specific sensitivity to sulfasalazine. Sulfasalazine triggers the mitochondrial accumulation of Bax and induces a collapse of the mitochondrial transmembrane potential (deltapsi(m)). Sulfasalazine causes cytochrome c release from mitochondria and subsequent activation of caspase-3 and downstream substrates. However, the pan-caspase inhibitor Z-VAD.fmk fails to inhibit sulfasalazine-induced apoptosis. Sulfasalazine stimulates mitochondrio-nuclear translocation of the novel apoptogenic factor apoptosis-inducing factor (AIF) and triggers large-scale DNA fragmentation, a characteristic feature of AIF-mediated apoptosis. Sulfasalazine-induced DeltaPsi(m) loss, AIF redistribution, and cell death are fully prevented by overexpression of Bcl-2. In conclusion, our data suggest that sulfasalazine-induced apoptosis of T-lymphocytes is mediated by mitochondrio-nuclear translocation of AIF and occurs in a caspase-independent fashion. Sulfasalazine-induced apoptosis by AIF and subsequent clearance of T-lymphocytes might thus provide the molecular basis for the beneficial therapeutic effects of sulfasalazine in the treatment of chronic inflammatory diseases.
Authors:
Susanne Liptay; Simone Fulda; Marta Schanbacher; Soizic Bourteele; Karine F Ferri; Guido Kroemer; Guido Adler; Klaus M Debatin; Roland M Schmid
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  137     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2002 Nov 
Date Detail:
Created Date:  2002-10-16     Completed Date:  2003-04-16     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  608-20     Citation Subset:  IM    
Affiliation:
Department of Paediatrics, University of Ulm, 89070 Ulm, Germany.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*,  physiology
Apoptosis Inducing Factor
Enzyme Activation / drug effects,  physiology
Flavoproteins / metabolism
Genes, bcl-2 / physiology
Humans
Jurkat Cells / drug effects,  metabolism
Membrane Proteins / metabolism
Sulfasalazine / pharmacology*
T-Lymphocytes / cytology*,  drug effects*,  metabolism
Chemical
Reg. No./Substance:
0/AIFM1 protein, human; 0/Apoptosis Inducing Factor; 0/Flavoproteins; 0/Membrane Proteins; 599-79-1/Sulfasalazine
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