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Molecular mechanisms of sulfasalazine-induced T-cell apoptosis
1. 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 hum...
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| Main Authors: | , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
| Publicado em: |
2002
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| Assuntos: | |
| Acesso em linha: | https://ncbi.nlm.nih.gov/pmc/articles/PMC1573529/ https://ncbi.nlm.nih.gov/pubmed/12381674 https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1038/sj.bjp.0704870 |
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| Resumo: | 1. 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. 2. Sulfasalazine induces apoptosis both in Jurkat cells, a human T-leukaemia cell line (ED(50) value ∼1.0 mM), and in primary human peripheral blood T-lymphocytes (ED(50) value ∼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. 3. Sulfasalazine triggers the mitochondrial accumulation of Bax and induces a collapse of the mitochondrial transmembrane potential (ΔΨ(m)). 4. 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. 5. 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. 6. Sulfasalazine-induced ΔΨ(m) loss, AIF redistribution, and cell death are fully prevented by overexpression of Bcl-2. 7. 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. |
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