Role for CD40-Mediated Activation of c-Rel and Maintenance of c-myc RNA Levels in Mitigating Anti-IgM-Induced Growth Arrest

Abstract CD40 crosslinking on B cells activates NF-κB and stress-activated protein kinase (SAPK) pathways. Since CD40 crosslinking rescues WEHI 231 B cells from anti-IgM-induced apoptosis, those pathways were likely candidates to be involved. Indeed, both signaling cascades predominated in anti-IgM-treated WEHI 231 cells, treated concurrently with anti-CD40 to rescue them from apoptosis. Crosslinking of CD40 activated the NF-κB proteins c-Rel and p50, but had no influence on their cytoplasmic steady state level. However, in contrast to—and even in the presence of—anti-IgM-mediated signals, engagement of CD40 resulted in a prolonged nuclear translocation of c-Rel, thereby allowing the formation of active NF-κB complexes. Consistent with this, the upstream regulatory element of the c-myc promoter, known to be regulated by NF-κB, was differently regulated after BCR ligation vs BCR plus CD40 crosslinking. The level of c-myc RNA was rapidly downregulated after BCR engagement, but persistent in the presence of CD40 signaling.