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The Journal of Immunology, 1998, 161: 3375-3383.
Copyright © 1998 by The American Association of Immunologists

Caspase-Independent Cell Death Induced by Anti-CD2 or Staurosporine in Activated Human Peripheral T Lymphocytes1

Olivier Déas*, Céline Dumont*, Marion MacFarlane{ddagger}, Matthieu Rouleau*, Chafika Hebib*, Francis Harper{dagger}, François Hirsch*, Bernard Charpentier*, Gerald M. Cohen2,{ddagger} and Anna Senik2,3,*

Centre National de la Recherche Scientifique, * Unité Propre de Recherche (UPR) 420, and {dagger} UPR 9044, Villejuif, France; and {ddagger} Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom

We examined the effects of the cell-permeable, broad spectrum peptide caspase inhibitors, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD.fmk), and BOC-Asp(OMe)-fluoromethyl ketone (BOC-D.fmk), on apoptosis induced by anti-CD2, anti-Fas, and the protein kinase inhibitor staurosporine in activated human peripheral T lymphocytes. We monitored ultrastructural, flow cytometric, and biochemical apoptotic changes, including externalization of phosphatidylserine, cleavage of poly(ADP-ribose) polymerase (PARP) and lamins, activation of caspase-3 and caspase-7, decrease in mitochondrial membrane potential, and DNA fragmentation. Z-VAD.fmk and BOC-D.fmk completely inhibited all the biochemical and ultrastructural changes of apoptosis in anti-Fas-treated cells. In marked contrast, neither Z-VAD.fmk nor BOC-D.fmk inhibited CD2- or staurosporine-mediated cell shrinkage, dilatation of the endoplasmic reticulum (seen in anti-CD2-treated cells), externalization of phosphatidylserine, and loss of mitochondrial membrane potential that accompanied cell death. However, these inhibitors did inhibit the cleavage of PARP and lamins and the formation of hypodiploid cells, and partially inhibited chromatin condensation. These results demonstrate that in activated T cells, anti-CD2 and staurosporine induce a caspase-independent cell death pathway that exhibits prominent cytoplasmic features of apoptosis. However, caspase activation is required for the proteolytic degradation of nuclear substrates such as PARP and lamins together with the DNA fragmentation and extreme chromatin condensation that occur in apoptotic cells.




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