Role of mitogen-activated protein kinases in activation-induced apoptosis of T cells

A member of the mitogen-activated protein (MAP) kinase family, Jun N-termin al kinase (JNK), has been implicated in regulating apoptosis in various cel l types. We have investigated the requirement for another type of MAP kinas e, extracellular signal-regulated protein kinase (ERK) in activation-induce d cell death (AICD) of T cells. AICD is the process by which recently activ ated T cells undergo apoptosis when restimulated through the T-cell antigen receptor. Here we show that both JNK and ERK are activated rapidly upon T- cell receptor (TCR) ligation prior to the onset of AICD. A chemical inhibit or of ERK activation, PD 098059, inhibits ERK activation and apoptosis. whi le JNK activation is not inhibited. This suggests that JNK activation is no t sufficient for apoptosis. TCR cross-linking induces expression of the apo ptosis-inducing factor, Fas ligand (FasL), and its expression correlates wi th ERK activation. In addition, apoptosis induced by direct ligation of the Fas receptor by anti-Fas antibody is not associated with ERK activation an d is not inhibited by PD 098059. These data suggest that ERK activation is an early event during T-cell apoptosis induced by antigen-receptor ligation , and is not involved in apoptosis per se but in the expression of Fast. MA P kinase family members may be similarly involved in inducing apoptosis sig nals in other cell types.