TGF beta 1 treatment of B cell lymphomas decreases c-myc gene expression and induces apoptosis. Since we have demonstrated NF-kappa/Rel factors play a key role in transcriptional control of c-myc, we explored the effects of TGF beta1 on WEHI 231 immature B cells. A reduction in NF-kappa B/Rel activity followed TGF beta 1 treatment. In WEHI 231 and CH33 cells, we observed an increase in I kappa B alpha, a specific NF-kappa B/Rel inhibitor, due to transcriptional induction. Engagement of surface CD40 or ectopic c-Rel led to maintenance of NF-kappa B/Rel and c-Myc expression and protection of WEHI 231 cells from TGF beta 1-mediated apoptosis. Ectopic c-Myc expression overrode apoptosis induced by TGF beta 1. Thus, downmodulation of NF-kappa B/Rel reduces c-Myc expression, which leads to apoptosis in these immature B cell models of clonal deletion. The inhibition of NF-kappa B/Rel activity represents a novel TGF beta signaling mechanism.