The extracellular signal-regulated kinase pathway is required for activation-induced cell death of T cells

Marcel R.M. Van Den Brink, Rosana Kapeller, Joanne C. Pratt, Jin Hong Chang, Steven J. Burakoff

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

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 daring 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.

Original languageEnglish
Pages (from-to)11178-11185
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number16
DOIs
StatePublished - 16 Apr 1999
Externally publishedYes

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