Molecular mechanisms of sulfasalazine‐induced T‐cell apoptosis

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Abstract
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 ∼1.0 mM), and in primary human peripheral blood T‐lymphocytes (ED50 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. Sulfasalazine triggers the mitochondrial accumulation of Bax and induces a collapse of the mitochondrial transmembrane potential (ΔΨm). 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 ΔΨm 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. British Journal of Pharmacology (2002) 137, 608–620. doi:10.1038/sj.bjp.0704870