Molecular mechanisms of sulfasalazine-induced T-cell apoptosis.
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.
Liptay
Susanne
S
Department of Paediatrics, University of Ulm, 89070 Ulm, Germany.
Fulda
Simone
S
Schanbacher
Marta
M
Bourteele
Soizic
S
Ferri
Karine F
KF
Kroemer
Guido
G
Adler
Guido
G
Debatin
Klaus M
KM
Schmid
Roland M
RM
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051033:Apoptosis Inducing Factor; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005420:Flavoproteins / Q000378:metabolism; D019254:Genes, bcl-2 / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D012460:Sulfasalazine