The extracellular signal-regulated kinase pathway is required for activation-induced cell death of T cells.
T cells can undergo activation-induced cell death (AICD) upon stimulation of the T cell receptor-CD3 complex. We found that the extracellular signal-regulated kinase (ERK) pathway is activated during AICD. Transient transfection of a dominant interfering mutant of mitogen-activated/extracellular signal-regulated receptor protein kinase kinase (MEK1) demonstrated that down-regulation of the ERK pathway inhibited FasL expression during AICD, whereas activation of the ERK pathway with a constitutively active MEK1 resulted in increased expression of FasL. We also found that pretreatment with the specific MEK1 inhibitor PD98059 prevented the induction of FasL expression during AICD and inhibited AICD. However, PD98059 had no effect on other apoptotic stimuli. We found only very weak ERK activity during Fas-mediated apoptosis (induced by Fas cross-linking). Furthermore, preincubation with the MEK1 inhibitor did not inhibit Fas-mediated apoptosis. Finally, we also demonstrated that pretreatment with the MEK1 inhibitor could delay and decrease the expression of the orphan nuclear steroid receptor Nur77, which has been shown to be essential for AICD. In conclusion, this study demonstrates that the ERK pathway is required for AICD of T cells and appears to regulate the induction of Nur77 and FasL expression during AICD.
van den Brink
M R
MR
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. mvandenb@bidmc.harvard.edu
Kapeller
R
R
Pratt
J C
JC
Chang
J H
JH
Burakoff
S J
SJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D048369:MAP Kinase Kinase 1; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D015854:Up-Regulation
D017252:CD3 Complex; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005419:Flavonoids; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one