Cell cycle- and activation-dependent regulation of cyclosporin A-induced T cell apoptosis.
The immunosuppressive agent cyclosporin A (CsA), which interferes with signal transduction pathways leading to cytokine gene transcription in activated T cells, was investigated regarding its ability to induce apoptosis in T cells undergoing cell cycle progression and activation. In Jurkat and peripheral CD4+ T cells, CsA was found to markedly induce apoptosis at the G0 phase of the cell cycle. Susceptibility to CsA-induced apoptosis progressively decreased during cell cycle progression to the S and G2/M phase, and subsequent T cell receptor- and mitogen-mediated activation totally abrogated CsA-induced apoptosis. Because CsA is an inhibitor of the chymotryptic peptidase activity of the proteasome, susceptibility to apoptosis induced by the proteasome inhibitor lactacystin was investigated under the same conditions. A progressive increase of the susceptibility of T cells to lactacystin-induced apoptosis during cell cycle progression and activation was demonstrated. Intracellular protein levels of the cyclin-dependent kinase inhibitor p27(Kip1)decreased from the G0 to G2/M phase and from the cycling to the activation state, but remained unchanged during the induction of apoptosis by CsA and lactacystin, suggesting a role of p27(Kip1)in the regulation of susceptibility to apoptosis during cell cycle progression and activation. Inhibition of CsA- but not lactacytin-induced apoptosis by overexpression of Bcl-2 in Jurkat T cells revealed that CsA and proteasome inhibitors activate different apoptotic pathways, while both CsA- and lactacystin-induced apoptosis were found to be dependent on caspase activation and independent of the FasL/Fas system. The results show that T cells can progressively regulate their susceptibility to apoptosis during cell cycle progression and activation in a stimulus-dependent manner, and suggest that lactacystin, but not CsA, is able to deplete activated T cells by apoptosis, a mechanism deemed necessary for the induction of allograft tolerance.
Naujokat
Cord
C
Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany. cord.naujokat@med.uni-heidelberg.de
Daniel
Volker
V
Bauer
Thomas M
TM
Sadeghi
Mahmoud
M
Opelz
Gerhard
G
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D016572:Cyclosporine / Q000494:pharmacology*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D046988:Proteasome Endopeptidase Complex; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D015853:Cysteine Proteinase Inhibitors; D007166:Immunosuppressive Agents; D009097:Multienzyme Complexes; C067713:lactacystin; D016572:Cyclosporine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine