NF-κB Is Required for Surface Ig-Induced Fas Resistance in B Cells

Abstract

The susceptibility of primary murine B cells to Fas-mediated apoptosis is regulated in a receptor-specific fashion. Whereas CD40 engagement produces marked sensitivity to Fas killing, engagement of the B cell Ag receptor blocks Fas signaling for cell death in otherwise Fas-sensitive, CD40-stimulated targets and thus induces Fas resistance. The signaling pathway that leads from B cell Ag receptor to Fas resistance has not been fully characterized, but has been shown to depend on new gene expression. NF-κB is activated following B cell Ag receptor engagement and is associated with antiapoptosis; thus, it would seem a likely candidate to mediate transcriptional activation for inducible Fas resistance. Inhibition of B cell Ag receptor signaling for NF-κB activation completely blocked induction of Fas resistance by anti-Ig, and this same phenotype was observed both with chemical inhibitors such as lactacystin and pyrrolidinedithiocarbamate as well as with an IκBα dominant negative TAT fusion protein. Antiapoptotic, NF-κB-responsive transcripts include two gene products previously implicated in mediating anti-Ig-induced Fas resistance, Bcl-xL and FLIP. B cell Ag receptor-induced up-regulation of both these gene products was blocked by NF-κB inhibition, suggesting a mechanism by which the loss of nuclear NF-κB alters the sensitivity of B cell Ag receptor-stimulated B cells to Fas-mediated apoptosis. These results indicate that activation of NF-κB plays a key role in mediating Fas resistance produced by B cell Ag receptor engagement.