Fas (CD95) ligation inhibits activation of NF-κB by targeting p65-Rel A in a caspase-dependent manner

Apoptosis is an important mechanism in T cell regulation. Initiation of apoptosis can be activated through two signaling pathways via proteins that bind the death domain, the MAPK-JNK pathway mediated by DAXX and the caspase pathway mediated by FADD. T cell proliferation is initiated by ligation of the T cell receptor (TCR) and activation of NF-κB, a transcription factor that has antiapoptotic functions. These pathways however are not isolated, and potential crosstalk between elements of the apoptotic pathway and growth pathway may be essential in determining cell survival. We studied the interaction between Fas- and the TCR-initiated pathways in Jurkat T cell as these pathways lead to opposing consequences. We show that Fas activation can inhibit TCR- and PMA/ionophore-initiated activation of NF-κB activity. The inhibition is caspase-dependent since an inhibitor of caspase activation, DEVD, can block the suppression of NF-κB activity following crosslinking of Fas. Analysis of the expression of the subunits of NF-κB revealed that the levels of p50 remained constant, whereas the levels of p65 were markedly decreased by crosslinking of Fas. These findings suggest that the Fas-ligation-mediated suppression preferentially targets p65 protein expression as a mechanism for suppression of antiapoptotic activities of NF-κB during apoptosis.